OX2R compounds

ABSTRACT

Methods and compositions for agonizing a type-2 orexin receptor (OX2R) in a cell determined to be in need thereof, including the general method of (a) administering to a subject a cyclic guanidinyl OX2R agonist and (b) detecting a resultant enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/648,933, filed Mar. 27, 2018, the disclosures of which are herebyincorporated by reference in their entireties for all purposes.

This invention was made with government support under Grant NumberNS068963 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

INTRODUCTION

This invention describes several chemically distinct classes ofnon-peptidic, small-molecule agonists for the type-2 orexin receptors(OX2R). Orexins are hypothalamic neuropeptides that are importantlyimplicated in sleep/wake control and body weight homeostasis.

Structurally distinct OX2R agonists are disclosed in U.S. Pat. No.8,871,794.

SUMMARY OF THE INVENTION

The invention provides OXR2 agonist compounds, and related compositions,methods of making and methods of use thereof. Aspects and embodiments ofthe invention are embodied in claims.

In one aspect, the present disclosure relates to a compound of formula(A):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y¹, Y², Y³, and Y⁴, are each independently N or CR⁶, wherein no        more than two of Y, Y², Y³, and Y⁴ are N;    -   W¹ and W² are each independently selected from aryl,        heterocyclyl, or heteroaryl, which are each optionally        substituted with one or more R¹⁰;    -   L is C₁-C₆ alkylene or C₂-C₆ alkenylene, optionally substituted        with one or more R⁷;    -   L² is C₁-C₆ alkylene or C₂-C₆ alkenylene, optionally substituted        with one or more R⁸;    -   R² is selected O, NH, NR¹¹;    -   R⁶ is selected hydrogen, halogen, —CN, —NO₂, —SC₁-C₆ alkyl,        —COR^(g), —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, or —C₁-C₆ haloalkoxy,    -   R⁷ is selected from halogen, —OH, —NR^(a)R^(b), —CN, —C₁-C₆        alkyl, —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —CH(OH)CH₂CN,        —C₁-C₃ alkylene-(C₁-C₆ alkoxy), —C₁-C₃ alkylene-(C₁-C₆        haloalkoxy), —C₁-C₃ alkylene-OCO(optionally substituted        heterocyclyl), —C₁-C₃ alkylene-OCOR⁹, —C₁-C₃ alkylene-OCOOR^(g),        —C₁-C₃ alkylene-NR^(a)R^(b), —C₁-C₃ alkylene-NR^(a)COR⁹, —C₁-C₃        alkylene-NR^(a)CO(optionally substituted heterocyclyl), —C₁-C₃        alkylene-NR^(a)COOR^(g), —C₁-C₃ alkylene-NR^(a)CONR^(a)R^(b),        —C₁-C₃ alkylene-CONR^(a)R^(b), —C₁-C₃ alkylene-CONR^(c)R^(d),        —CONR^(a)R^(b), —CONR^(c)R^(d), —(C₁-C₃ alkylene)-O—(C₁-C₃        alkylene)-OH, —(C₁-C₃ alkylene)-O—(C₁-C₃ alkylene)-CN, —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₄ haloalkyl), —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-S—(C₁-C₃ alkyl), —C₁-C₃        alkylene-S(C₁-C₆ alkyl), —C₁-C₃ alkylene-SO(C₁-C₆ alkyl), —C₁-C₃        alkylene-SO₂(C₁-C₆ alkyl), —C₁-C₃ alkylene-SO₂R¹², or        hetercyclyl optionally substituted with R¹⁰;    -   R⁸ is selected from —OH, —CN, —NO₂, —COR^(g), oxo, —C₁-C₆ alkyl,        —C₁-C₆ alkylene-OH, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl,    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —COOH, —CO(C₁-C₃ alkyl),        —CO(C₁-C₃ haloalkyl), —CO(C₃-C₈ cycloalkyl), —CO(C₂-C₄ alkenyl),        —CO(C₁-C₆ alkylene)-OH, —CO(C₁-C₆ alkylene)-(C₁-C₆ alkoxy),        —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f), —CO(C₁-C₃        alkylene)-NR^(e)SR^(f), —CO(C₁-C₃ alkylene)-NR^(e)SOR^(g),        —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f), —CO(C₂-C₃ alkenyl),        —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b),    -   R¹⁰ is halogen, —CN, oxo, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆        alkoxy, —C₁-C₆ haloalkoxy, —SC₁-C₆ alkyl, —S—S—(C₁-C₆ alkyl), or        optionally substituted phenyl;    -   R¹¹ is —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₃        alkylene-OH, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), —COO(C₁-C₆ alkyl);    -   alternatively, R¹¹ and R⁷ together form a 5- to 7-membered ring,        which is optionally substituted with R¹⁰;    -   R¹² is —OH, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        —C₁-C₆ alkoxy, phenyl, benzyl, —NR^(a)R^(b), —CONR^(a)R^(b), or        —NR^(a)COR^(g);    -   n is 0, 1, or 2.

In one embodiment of the compounds of formula (A), R² is NH.

In one embodiment of the compounds of formula (A), Y³ and Y⁴, are eachindependently CH or CR⁶.

In one embodiment of the compounds of formula (A), Y¹ and Y² is N andthe other is CH or CR⁶.

In one embodiment of the compounds of formula (A), Y, Y², Y³ and Y⁴, areeach CH or CR⁶.

In one embodiment of the compounds of formula (A), R⁶ is halogen,methyl, —CH₂F, —CHF₂, or —CF₃.

In one embodiment of the compounds of formula (A), R¹⁰ is halogen,methyl, —CH₂F, —CHF₂, or —CF₃.

In one embodiment of the compounds of formula (A), L² is C₁ alkeylene orC₄ alkenylene, optionally substituted with one R⁸. In one embodiment, L²is C₁ alkeylene, optionally substituted with one R⁸.

In one embodiment of the compounds of formula (A), R⁸ is methyl, ethyl,isopropyl, cyclopropyl, cyclobutyl, —CH₂F, —CHF₂, or —CF₃.

In one embodiment of the compounds of formula (A), L is C₂ alkeyleneoptionally substituted with one R⁷.

In one embodiment of the compounds of formula (A), -L¹-W is —CHR⁷CH₂—W¹.

In one embodiment of the compounds of formula (A), W¹ is phenyloptionally substituted with R¹⁰.

In one embodiment of the compounds of formula (A), W² is phenyloptionally substituted with R¹⁰.

In one embodiment of the compounds of formula (A), R⁷ is —C₁-C₃alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃ alkylene-(C₁-C₆ alkoxy), —C₁-C₃alkylene-NR^(a)R^(b), —C₁-C₃ alkylene-OCO(optionally substitutedheterocyclyl), —C₁-C₃ alkylene-OCOR⁹, —C₁-C₃ alkylene-NR^(a)COR⁹, —C₁-C₃alkylene-NR^(a)CO(optionally substituted heterocyclyl), —C₁-C₃alkylene-NR^(a)CONR^(a)R^(b), —CONR^(c)R^(d), —(C₁-C₃ alkylene)-O—(C₁-C₃alkylene)-OH, —(C₁-C₃ alkylene)-O—(C₁-C₃ alkylene)-CN, —(C₁-C₃alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), —C₁-C₃ alkylene-S(C₁-C₆alkyl), —C₁-C₃ alkylene-SO(C₁-C₆ alkyl), or —C₁-C₃ alkylene-SO₂(C₁-C₆alkyl). In one embodiment, R⁷ is —CH₂OH, —CH₂NH₂, —CH(CH₃)OH, —CH₂CN,—CH₂(C₁-C₃ alkoxy), —CH₂OCO(optionally substituted heterocyclyl),—CH₂OCOR^(g), —CH₂NR^(a)COR⁹, —CH₂NR^(a)CO(optionally substitutedheterocyclyl), —CH₂NR^(a)CONR^(a)R^(b), —CONR^(c)R^(d), —CH₂O—(C₁-C₃alkylene)-OH, —CH₂O—(C₁-C₃ alkylene)-CN, —CH₂O—(C₁-C₃ alkylene)-O—(C₁-C₃alkyl), —CH₂S(C₁-C₆ alkyl), —CH₂SO(C₁-C₆ alkyl), or —CH₂SO₂(C₁-C₆alkyl). In one embodiment, R⁷ is —CH₂OH, —CH₂NH₂, —CH(CH₃)OH, —CH₂CN,—CH₂OCH₃, —CH₂OCO(optionally substituted azetidinyl), —CH₂OCOCH₂OH,—CH₂NR^(a)COCH₂OH, —CH₂NHCOCH₂NHCH₃, —CH₂NR^(a)CO(azyridinyl),—CH₂NR^(a)CONH₂, —CONR^(c)R^(d), —CH₂O—(C₁-C₃ alkylene)-OH, —CH₂O—(C₁-C₃alkylene)-CN, —CH₂O—(C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), —CH₂S(C₁-C₃alkyl), —CH₂SO(C₁-C₃ alkyl), or —CH₂SO₂(C₁-C₃ alkyl). In one embodiment,R⁷ is —CH₂OH, —CH₂NH₂, —CH(CH₃)OH, —CH₂CN, —CH₂OCH₃, —CH₂OCOCH₂OH,—CH₂NHCOCH₂OH, —CH₂N(CH₃)COCH₂OH, —CH₂NHCOCH₂NHCH₃, —CH₂NHCONH₂,—CH₂OCH₂OH, —CH₂OCH₂CH₂OH, —CH₂OCH₂CN, —CH₂OCH₂CH₂CN, —CH₂OH₂OCH₃,—CH₂OH₂CH₂OCH₃, —CH₂SCH₃, —CH₂SOCH₃, or —CH₂SO₂CH₃. In one embodiment R⁷is —CONR^(c)R^(d) selected from

each of which are optionally substituted with halogen, —CN, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkylene-OH, or —C₁-C₆ alkylene-NH₂.

In one aspect, the present disclosure relates to a compound of formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y¹ and Y² are each independently N or CR⁶;    -   Ar¹ and Ar² are each independently C5-C10 aryl or 5- to        10-membered heteroaryl comprising one, two, or three heteroatoms        selected from N, O, or S, each of which are optionally        substituted with one or more R¹⁰;    -   R¹ is —OH, —C₁-C₄ alkoxy, —C₁-C₄ haloalkoxy, —NR^(a)R^(b),        —NR^(a)COR⁹, —NR^(a)CO(optionally substituted heterocyclyl),        —CONR^(a)R^(b), —CONR^(c)R^(d), SO₂R¹², —O—(C₁-C₃        alkylene)-O—(C₁-C₄ alkyl) or —O—(C₁-C₃ alkylene)-O—(C₁-C₄        haloalkyl);    -   R² is selected O, NH, or NR¹¹,    -   R³ is H or methyl;    -   R⁴ is H, —CN, —NO₂, —COR^(g), —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, or        —C₃-C₄ cycloalkyl;    -   R⁵ is H or methyl;    -   R⁶ is selected H, halogen, —CN, —NO₂, —SCH₃, —COR^(g), —C₁-C₄        alkyl, —C₁-C₄ haloalkyl, —C₃-C₄ cycloalkyl, —C₁-C₄ alkoxy, or        —C₁-C₄ haloalkoxy;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₄        alkyl, —C₁-C₄ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl),        —CO(CH₂)_(n)(cycloalkyl), —CO(CH₂)_(n)(optionally substituted        aryl), —CO(CH₂)_(n)(optionally substituted heterocyclyl), or        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R⁹ is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, benzyl,    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), —C₁-C₃ alkylene-NR^(a)R^(b),    -   R¹⁰ is halogen, —CN, oxo, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆        alkoxy, —C₁-C₆ haloalkoxy, —S—S—(C₁-C₆ alkyl), or optionally        substituted phenyl;    -   R¹¹ is —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, —C₁-C₄ alkoxy, or        COO(C₁-C₄ alkyl);    -   alternatively, R¹¹ and R⁷ together form a 5- to 7-membered ring,        which is optionally substituted with R¹⁰;    -   R¹¹ is —OH, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        —C₁-C₆ alkoxy, phenyl, benzyl, —NR^(a)R^(b), —CONR^(a)R^(b), or        —NR^(a)COR^(h);    -   n is 0, 1, or 2; and    -   m is 0, 1, or 2.

In one embodiment of the compounds of formula (A), Ar¹ is phenyloptionally substituted with one or more R¹¹.

In one embodiment of the compounds of formula (A), R¹⁰ is halogen, —CN,—C₁-C₄ alkyl, or —C₁-C₄ fluoroalkyl.

In one embodiment of the compounds of formula (A), Ar¹ is4-methylphenyl.

In one embodiment of the compounds of formula (A), Ar² is4-methylphenyl.

In one embodiment of the compounds of formula (A),

-   -   R¹ is —OH, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —NR^(a)R^(b),        —NHCOR⁹, or —CONR^(a)R^(b);    -   R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl or —C₁-C₄        fluoroalkyl; and    -   R⁹ is —C₁-C₄ alkyl or —C₁-C₄ fluoroalkyl.

In one embodiment of the compounds of formula (A),

-   -   R¹ is —OH, —OCH₃, C₁-C₄ haloalkoxy, —NR^(a)R^(b), —NHCOR⁹, or        —CONR^(a)R^(b), —OCH₂O—(C₁-C₄ alkyl) or —OCH₂O—(C₁-C₄        haloalkyl);    -   R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl or —C₁-C₄        fluoroalkyl; and    -   R⁹ is —C₁-C₄ alkyl or —C₁-C₄ fluoroalkyl.

In one embodiment of the compounds of formula (A),

-   -   R¹ is —OH, —OCH₃, —NHCH₃, —N(CH₃)₂, —NHSO₂R¹², or —NHCOR¹²; and    -   R¹² is —CH₃, —CH₂CH₃, isopropyl, —CF₃, —OH, —OCH₃, —OCH₂CH₃,        cyclopropyl, phenyl, benzyl, —NR^(a)R^(b), —CONR^(a)R^(b), or        —NR^(a)COR¹.

In one embodiment of the compounds of formula (A), R² is O, NH, or NCH₃.

In one embodiment of the compounds of formula (A), R³ is H.

In one embodiment of the compounds of formula (A), R⁴ is H or methyl.

In one embodiment of the compounds of formula (A), R⁶ is H, halogen,—CH₃, —CF₃, —CN, —SCH₃, t-butyl, —OCH₃, or —OCF₃.

In one aspect, the present disclosure relates to compounds of formula(B):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y¹ and Y² are each independently N or CR⁶;    -   W¹ and W² are each independently selected from 5- to 10-membered        aryl, heterocyclyl, or heteroaryl, which are each optionally        substituted with one or more R¹⁰;    -   R² is selected O or NH;    -   R⁶ is selected hydrogen, halogen, —CN, —C₁-C₃ alkyl, —C₃-C₆        cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, or —C₁-C₃ haloalkoxy,    -   R⁷ is selected from halogen, —OH, —NR^(a)R^(b), —CN, —C₁-C₆        alkyl, —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —CH(OH)CH₂CN,        —C₁-C₃ alkylene-(C₁-C₆ alkoxy), —C₁-C₃ alkylene-(C₁-C₆        haloalkoxy), —C₁-C₃ alkylene-OCO(optionally substituted        heterocyclyl), —C₁-C₃ alkylene-OCOR⁹, —C₁-C₃ alkylene-OCOOR^(g),        —C₁-C₃ alkylene-NR^(a)R^(b), —C₁-C₃ alkylene-NR^(a)COR⁹, —C₁-C₃        alkylene-NR^(a)CO(optionally substituted heterocyclyl), —C₁-C₃        alkylene-NR^(a)COOR^(g), —C₁-C₃ alkylene-NR^(a)CONR^(a)R^(b),        —C₁-C₃ alkylene-CONR^(a)R^(b), —C₁-C₃ alkylene-CONR^(c)R^(d),        —CONR^(a)R^(b), —CONR^(c)R^(d), —(C₁-C₃ alkylene)-O—(C₁-C₃        alkylene)-OH, —(C₁-C₃ alkylene)-O—(C₁-C₃ alkylene)-CN, —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₄ haloalkyl), —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-S—(C₁-C₃ alkyl), —C₁-C₃        alkylene-S(C₁-C₆ alkyl), —C₁-C₃ alkylene-SO(C₁-C₆ alkyl), or        —C₁-C₃ alkylene-SO₂(C₁-C₆ alkyl);    -   R⁸ is selected from —OH, —CN, oxo, —C₁-C₆ alkyl, C₁-C₆        alkylene-OH, —C₁-C₆ haloalkyl, or —C₃-C₆ cycloalkyl,    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl), or        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, benzyl,    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), —C₁-C₃ alkylene-NR^(a)R^(b),    -   R¹⁰ is halogen, —CN, oxo, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆        alkoxy, —C₁-C₆ haloalkoxy, —S—S—(C₁-C₆ alkyl), or optionally        substituted phenyl;    -   R¹¹ is —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₃        alkylene-OH, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), or —COO(C₁-C₆        alkyl);    -   alternatively, R¹¹ and R⁷ together form a 5- to 7-membered ring,        which is optionally substituted with R¹⁰; and    -   n is 0, 1, or 2.

In one aspect, the present disclosure relates to compounds of formula(C):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y¹ and Y² are each independently N or CR⁶;    -   W¹ and W² are each independently selected from 5- to 10-membered        aryl, heterocyclyl, or heteroaryl, which are each optionally        substituted with one or more R¹⁰;    -   R² is selected O or NH;    -   R⁶ is selected hydrogen, halogen, —CN, —C₁-C₃ alkyl, —C₃-C₆        cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, or —C₁-C₃ haloalkoxy,    -   R⁷ is selected from —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN,        —C₁-C₃ alkylene-(C₁-C₆ alkoxy), —C₁-C₃ alkylene-NR^(a)R^(b),        —C₁-C₃ alkylene-OCO(optionally substituted heterocyclyl), —C₁-C₃        alkylene-OCOR⁹, —C₁-C₃ alkylene-NR^(a)COR⁹, —C₁-C₃        alkylene-NR^(a)CO(optionally substituted heterocyclyl), —C₁-C₃        alkylene-NR^(a)CONR^(a)R^(b), —CONR^(c)R^(d), —(C₁-C₃        alkylene)-O—(C₁-C₃ alkylene)-OH, —(C₁-C₃ alkylene)-O—(C₁-C₃        alkylene)-CN, —(C₁-C₃ alkylene)-O—(C₁-C₃ alkylene)-O—(C₁-C₃        alkyl), —C₁-C₃ alkylene-S(C₁-C₆ alkyl), —C₁-C₃ alkylene-SO(C₁-C₆        alkyl), or —C₁-C₃ alkylene-SO₂(C₁-C₆ alkyl);    -   R⁸ is selected from —OH, —CN, oxo, —C₁-C₆ alkyl, C₁-C₆        alkylene-OH, —C₁-C₆ haloalkyl, —C₃-C₆ cycloalkyl,    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R⁹ is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, benzyl,    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), —C₁-C₃ alkylene-NR^(a)R^(b),    -   R¹⁰ is halogen, —CN, oxo, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆        alkoxy, —C₁-C₆ haloalkoxy, —S—S—(C₁-C₆ alkyl), or optionally        substituted phenyl;    -   R¹¹ is —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₃        alkylene-OH, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), —COO(C₁-C₆ alkyl);        and    -   n is 0, 1, or 2.

In one aspect, the present disclosure relates to compounds of formula(D):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y¹ and Y² are each independently N or CR⁶;    -   W¹ and W² are each phenyl, which are each optionally substituted        with one or more R¹⁰;    -   R² is selected O or NH;    -   R⁶ is selected hydrogen, halogen, —CN, —C₁-C₃ alkyl, —C₃-C₆        cycloalkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, or —C₁-C₃ haloalkoxy,    -   R⁷ is selected from —CH₂OH, —CH₂NH₂, —CH(CH₃)OH, —CH₂CN,        —CH₂(C₁-C₃ alkoxy), —CH₂OCO(optionally substituted        heterocyclyl), —CH₂OCOR⁹, —CH₂NR^(a)COR⁹,        —CH₂NR^(a)CO(optionally substituted heterocyclyl),        —CH₂NR^(a)CONR^(a)R^(b), —CONR^(c)R^(d), —CH₂O—(C₁-C₃        alkylene)-OH, —CH₂O—(C₁-C₃ alkylene)-CN, —CH₂O—(C₁-C₃        alkylene)-O—(C₁-C₃ alkyl), —CH₂S(C₁-C₆ alkyl), —CH₂SO(C₁-C₆        alkyl), or —CH₂SO₂(C₁-C₆ alkyl);    -   R⁸ is selected from —OH, —CN, oxo, —C₁-C₆ alkyl, C₁-C₆        alkylene-OH, —C₁-C₆ haloalkyl, or —C₃-C₆ cycloalkyl,    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R⁹ is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b),    -   R¹⁰ is halogen, —CN, oxo, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆        alkoxy, —C₁-C₆ haloalkoxy, —S—S—(C₁-C₆ alkyl), or optionally        substituted phenyl;    -   R¹¹ is —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₃        alkylene-OH, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), or —COO(C₁-C₆        alkyl); and    -   n is 0, 1, or 2.

In one embodiment of the compounds of formula (A) or (B)-(D), wherein R⁷is —CH₂OH, —CH₂NH₂, —CH(CH₃)OH, —CH₂CN, —CH₂OCH₃, —CH₂OCO(optionallysubstituted azetidinyl), —CH₂OCOCH₂OH, —CH₂NR^(a)COCH₂OH,—CH₂NHCOCH₂NHCH₃, —CH₂NR^(a)CO(azyridinyl), —CH₂NR^(a)CONH₂,—CONR^(c)R^(d), —CH₂O—(C₁-C₃ alkylene)-OH, —CH₂O—(C₁-C₃ alkylene)-CN,—CH₂O—(C₁-C₃ alkylene)-O—(C₁-C₃ alkyl), —CH₂S(C₁-C₃ alkyl), —CH₂SO(C₁-C₃alkyl), or —CH₂SO₂(C₁-C₃ alkyl). In one embodiment, R⁷ is —CH₂OH,—CH₂NH₂, —CH(CH₃)OH, —CH₂CN, —CH₂OCH₃, —CH₂OCOCH₂OH, —CH₂NHCOCH₂OH,—CH₂N(CH₃)COCH₂OH, —CH₂NHCOCH₂NHCH₃, —CH₂NHCONH₂, —CH₂OCH₂OH,—CH₂OCH₂CH₂OH, —CH₂OCH₂CN, —CH₂OCH₂CH₂CN, —CH₂OH₂OCH₃, —CH₂OH₂CH₂OCH₃,—CH₂SCH₃, —CH₂SOCH₃, or —CH₂SO₂CH₃. In one embodiment, R⁷ is—CONR^(c)R^(d) selected from

each of which are optionally substituted with halogen, —CN, —C₁-C₆alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkylene-OH, or —C₁-C₆ alkylene-NH₂.

In one embodiment of the compounds of formula (A) or (B)-(D), R¹⁰ ishalogen, —CN, —C₁-C₃ alkyl, —C₁-C₃ haloalkyl, —C₁-C₃ alkoxy, —C₁-C₃haloalkoxy,

In one embodiment of the compounds of formula (A) or (B)-(D), W¹ is4-methylphenyl.

In one embodiment of the compounds of formula (A) or (B)-(D), W² is4-methylphenyl.

In one aspect, the present disclosure relates to compounds of formula(II):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is aryl or heteroaryl, optionally substituted with one or        more R^(1a);    -   R² is aryl or heteroaryl, optionally substituted with one or        more R^(2a);    -   R³ is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or        heteroaryl, optionally substituted with one or more R^(3a); and    -   R^(1a), R^(2a), and R^(3a) is each independently selected from        halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy,        —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR^(g), —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g),        —OCO(optionally substituted heterocyclyl), —NR^(a)COR⁹,        —NR^(a)CO(optionally substituted heterocyclyl), —NR^(a)COOR^(g),        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl; and    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b).

In one embodiment of the compounds of formula (II), wherein R¹ isphenyl, optionally substituted with one or more R^(1a).

In one embodiment of the compounds of formula (II), R² is phenyl,optionally substituted with one or more R^(2a).

In one embodiment of the compounds of formula (II), R³ is phenyl,optionally substituted with one or more R^(3a).

In one embodiment of the compounds of formula (II), R^(1a) is —NO₂.

In one embodiment of the compounds of formula (II), R^(2a) is halogen,C₁-C₃ alkyl, —S(C₁-C₃ alkyl), —NH₂, —NH(C₁-C₃ alkyl), or —N(C₁-C₃alkyl)₂.

In one embodiment of the compounds of formula (II), R^(3a) is halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O(C₁-C₃ alkyl), —S(C₁-C₃ alkyl),—SO(C₁-C₃ alkyl), —SO₂(C₁-C₃ alkyl), —CN, —NO₂, —NH₂, —NH(C₁-C₃ alkyl),or —N(C₁-C₃ alkyl)₂.

In one aspect, the present disclosure relates to compounds of formula(III):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R² is aryl or heteroaryl, optionally substituted with one or        more R^(2a);    -   R³ is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or        heteroaryl, optionally substituted with one or more R^(3a); and    -   R^(1a), R^(2a), and R^(3a) is each independently selected from        halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy,        —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR^(g), —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g),        —OCO(optionally substituted heterocyclyl), —NR^(a)COR⁹,        —NR^(a)CO(optionally substituted heterocyclyl), —NR^(a)COOR^(g),        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(A) is selected from H, halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl,        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,        —C₁-C₆ haloalkoxy, —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆        alkyl), —SO₂(C₁-C₆ alkyl), —COR⁹, —NR^(a)R^(b), —OCOR⁹,        —OCOOR^(g), —OCO(optionally substituted heterocyclyl),        —NR^(a)COR⁹, —NR^(a)CO(optionally substituted heterocyclyl),        —NR^(a)COOR⁹, —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b),        —CONR^(c)R^(d), heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b); and    -   n is 0, 1, 2, 3, or 4.

In one embodiment of the compounds of formula (III), R^(A) is H or —NO₂.

In one embodiment of the compounds of formula (III), n is 0 or 1.

In one embodiment of the compounds of formula (III), R² is phenyl,optionally substituted with one or more R^(2a).

In one embodiment of the compounds of formula (III), R³ is phenyl,optionally substituted with one or more R^(3a).

In one embodiment of the compounds of formula (III), R^(2a) is halogen,C₁-C₃ alkyl, —S(C₁-C₃ alkyl), —NH₂, —NH(C₁-C₃ alkyl), or —N(C₁-C₃alkyl)₂.

In one embodiment of the compounds of formula (III), R^(3a) is halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O(C₁-C₃ alkyl), —S(C₁-C₃ alkyl),—SO(C₁-C₃ alkyl), —SO₂(C₁-C₃ alkyl), —CN, —NO₂, —NH₂, —NH(C₁-C₃ alkyl),or —N(C₁-C₃ alkyl)₂.

In one aspect, the present disclosure relates to compounds of formula(IV):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is aryl or heteroaryl, optionally substituted with one or        more R^(1a);    -   R³ is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or        heteroaryl, optionally substituted with one or more R^(3a); and    -   R^(1a), R^(2a), and R^(3a) is each independently selected from        halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy,        —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR^(g), —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g),        —OCO(optionally substituted heterocyclyl), —NR^(a)COR⁹,        —NR^(a)CO(optionally substituted heterocyclyl), —NR^(a)COOR^(g),        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(B) is selected from H, halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl,        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,        —C₁-C₆ haloalkoxy, —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆        alkyl), —SO₂(C₁-C₆ alkyl), —COR⁹, —NR^(a)R^(b), —OCOR⁹,        —OCOOR^(g), —OCO(optionally substituted heterocyclyl),        —NR^(a)COR⁹, —NR^(a)CO(optionally substituted heterocyclyl),        —NR^(a)COOR^(g), —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b),        —CONR^(c)R^(d), heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b); and    -   m is 0, 1, 2, 3, or 4.

In one embodiment of the compounds of formula (IV), R^(B) is H, halogen,C₁-C₃ alkyl, —S(C₁-C₃ alkyl), —NH₂, —NH(C₁-C₃ alkyl), or —N(C₁-C₃alkyl)₂In one embodiment, R^(B) is H, Me, Cl, F, —SCH₃, or —N(CH₃)₂.

In one embodiment of the compounds of formula (IV), m is 0 or 1.

In one embodiment of the compounds of formula (IV), R¹ is phenyl,optionally substituted with one or more R^(1a).

In one embodiment of the compounds of formula (IV), R³ is phenyl,optionally substituted with one or more R^(3a).

In one embodiment of the compounds of formula (IV), R^(1a) is —NO₂.

In one embodiment of the compounds of formula (IV), R^(3a) is halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O(C₁-C₃ alkyl), —S(C₁-C₃ alkyl),—SO(C₁-C₃ alkyl), —SO₂(C₁-C₃ alkyl), —CN, —NO₂, —NH₂, —NH(C₁-C₃ alkyl),or —N(C₁-C₃ alkyl)₂.

In one aspect, the present disclosure relates to compounds of formula(V):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is aryl or heteroaryl, optionally substituted with one or        more R^(1a);    -   R² is aryl or heteroaryl, optionally substituted with one or        more R^(2a);    -   R³ is C₁-C₆ alkyl, cyclohexyl, phenyl, benzyl, —CH₂CH₂-phenyl,        benzodioxolyl, or thienyl, optionally substituted with one or        more R^(3a);    -   R^(1a), R^(2a), and R^(3a) is each independently selected from        halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy,        —C₃-C₆ cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR⁹, —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g), —OCO(optionally        substituted heterocyclyl), —NR^(a)COR⁹, —NR^(a)CO(optionally        substituted heterocyclyl), —NR^(a)COOR^(g),        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b).

64. The compound of claim 63, wherein R³ is methyl, cyclohexyl, phenyl,benzyl, —CH₂CH₂-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,3-fluorophenyl, 4-fluorophenyl, 4-nitrophenyl, 3-chlorophenyl,4-chlorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-dimethylaminophenyl,4-trifluoromethylphenyl, 4-t-butylphenyl, 4-n-butylphenyl,4-methoxylphenyl, 4-methoxylphenyl, 4-methylsulfonylphenyl,4-methylthiophenyl, 2-thienyl, or benzodioxolyl.

In one embodiment of the compounds of formula (V), R³ is 4-methylphenyl,4-dimethylaminophenyl, 4-t-butylphenyl, or 4-n-butylphenyl.

In one embodiment of the compounds of formula (V), R¹ is phenyl,optionally substituted with one or more R^(1a).

In one embodiment of the compounds of formula (V), R² is phenyl,optionally substituted with one or more R^(2a).

In one embodiment of the compounds of formula (V), R³ is phenyl,optionally substituted with one or more R^(3a).

In one embodiment of the compounds of formula (V), R^(1a) is —NO₂.

In one embodiment of the compounds of formula (V), R^(2a) is halogen,C₁-C₃ alkyl, —S(C₁-C₃ alkyl), —NH₂, —NH(C₁-C₃ alkyl), or —N(C₁-C₃alkyl)₂.

In one embodiment of the compounds of formula (V), R^(3a) is halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O(C₁-C₃ alkyl), —S(C₁-C₃ alkyl),—SO(C₁-C₃ alkyl), —SO₂(C₁-C₃ alkyl), —CN, —NO₂, —NH₂, —NH(C₁-C₃ alkyl),or —N(C₁-C₃ alkyl)₂. In one embodiment, R^(3a) is C₁-C₄ alkyl or—N(C₁-C₃ alkyl)₂.

In one aspect, the present disclosure relates to compounds of formula(VI):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R^(3a) is each independently selected from halogen, —OH, —CN,        —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆        haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy, —C₃-C₆ cycloalkyl,        —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl), —COR⁹,        —NR^(a)R^(b), —OCOR⁹, —OCOOR⁹, —OCO(optionally substituted        heterocyclyl), —NR^(a)COR⁹, —NR^(a)CO(optionally substituted        heterocyclyl), —NR^(a)COOR^(g), —NR^(a)CONR^(a)R^(b),        —CONR^(a)R^(b), —CONR^(c)R^(d), heterocyclyl, heteroaryl, or        aryl;    -   R^(A) and R^(B) are each independently selected from H, halogen,        —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,        —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy, —C₃-C₆        cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR^(g), —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g),        —OCO(optionally substituted heterocyclyl), —NR^(a)COR⁹,        —NR^(a)CO(optionally substituted heterocyclyl), —NR^(a)COOR⁹,        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)(cycloalkyl),        —CO(CH₂)_(n)(optionally substituted aryl),        —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(e) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b); and    -   p is 0, 1, 2, 3, or 4.

In one embodiment of the compounds of formula (VI), R^(A) is H or —NO₂.

In one embodiment of the compounds of formula (VI), R^(B) is H, halogen,C₁-C₃ alkyl, —S(C₁-C₃ alkyl), —NH₂, —NH(C₁-C₃ alkyl), or —N(C₁-C₃alkyl)₂. In one embodiment, R^(B) is H, Me, Cl, F, —SCH₃, or —N(CH₃)₂.

In one embodiment of the compounds of formula (VI), R^(3a) is halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O(C₁-C₃ alkyl), —S(C₁-C₃ alkyl),—SO(C₁-C₃ alkyl), —SO₂(C₁-C₃ alkyl), —CN, —NO₂, —NH₂, —NH(C₁-C₃ alkyl),or —N(C₁-C₃ alkyl)₂. In one embodiment, R^(3a) is C₁-C₄ alkyl or—N(C₁-C₃ alkyl)₂.

In one aspect, the present disclosure relates to compounds of formula(VII):

or a pharmaceutically acceptable salt thereof, wherein

-   -   L¹ is —NR⁷C(═O)—, —CONR⁷—, —CH₂C(═O)—, —C(═O)CH₂—, —OC(═O)—,        —C(═O)O—, —SC(═O)—, —C(═O)S—, —NRC(═O)—, —CH₂NR⁷—, —CH₂CH₂—,        —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—, —NR⁷SO₂—, —SO₂NR⁷—, —CH₂SO₂—,        —SO₂CH₂—, —OSO₂—, —SO₂O—, —NR⁷—,    -   L² is —SO₂—, —C(═O)—, —CH₂—, —CH₂CH₂—, —CHR⁶—,    -   W is arylene or heteroarylene, each optionally substituted with        one or more R⁴;    -   R¹ is aryl or heteroaryl, each optionally substituted with one        or more R⁴;    -   R² is selected NH₂, or NHR¹¹;    -   R³ is halogen, —CN, —NO₂, —SCH₃, —COR⁵, —C₁-C₆ alkyl, —C₃-C₆        cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —C₁-C₆ haloalkoxy,    -   R⁴ is halogen, —CN, —NO₂, —SCH₃, —COR⁵, —C₁-C₆ alkyl, —C₃-C₆        cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —C₁-C₆ haloalkoxy;    -   R⁵ is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, or —C₁-C₆ haloalkyl;    -   R⁶ is selected halogen, —CN, —NO₂, —SCH₃, —COR⁵, —C₁-C₆ alkyl,        —C₃-C₆ cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or —C₁-C₆        haloalkoxy,    -   R⁷ is —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₃        alkylene-OH, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), —COO(C₁-C₆ alkyl);        and    -   n is 0, 1, 2, 3, 4, or 5.

In one embodiment of the compounds of formula (VII), W is phenylene,optionally substituted with one or two R⁴. In one embodiment, W is

In one embodiment of the compounds of formula (VII), W is 5- or6-membered heteroarylene, optionally substituted with one or two R⁴. Inone embodiment, W is divalent oxazole or isoxazole, optionallysubstituted with one or two R⁴. In one embodiment, W is

In one embodiment of the compounds of formula (VII), R¹ is phenyl,optionally substituted with one or two R⁴.

In one embodiment of the compounds of formula (VII), —W—R¹ is

In one embodiment of the compounds of formula (VII), R⁴ is selected fromhalogen, —C₁-C₃ alkyl, —C₁-C₃ haloalkyl, or C₁-C₃ alkoxy.

In one embodiment of the compounds of formula (VII), L¹ is —NHC(═O)—,—CONH—, —NCH₃C(═O)—, —CONCH₃—, —CH₂C(═O)—, —C(═O)CH₂—, —OC(═O)—,—C(═O)O—, —SC(═O)—, —C(═O)S—, —NHC(═O)—, —CH₂NH—, —NCH₃C(═O)—,—CH₂NCH₃—, —CH₂CH₂—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—, —NHSO₂—, —SO₂NH—,—NCH₃SO₂—, —SO₂NCH₃—, —CH₂SO₂—, —SO₂CH₂—, —OSO₂—, or —SO₂O—.

In one embodiment of the compounds of formula (VII), R² is —NH₂.

In one embodiment of the compounds of formula (VII), R³ is selected fromhalogen, —C₁-C₃ alkyl, —C₁-C₃ haloalkyl, or C₁-C₃ alkoxy. In oneembodiment, R³ is selected from halogen, methyl, methoxy, or —CF₃.

In one embodiment of the compounds of formula (VII), n is 1 and R³ ispara to L².

In one aspect, the present disclosure relates to compounds of formula(VIII):

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or        heteroaryl, optionally substituted with one or more R^(1a);    -   R² is aryl or heteroaryl, optionally substituted with one or        more R^(2a);    -   R³ is H, or —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy,        —C₃-C₆ cycloalkyl, aryl or heteroaryl, optionally substituted        with one or more R^(3a)    -   R^(1a) is each independently selected from halogen, —OH, —CN,        —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆        haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy, —C₃-C₆ cycloalkyl,        —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆ alkyl), —COR^(g),        —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g), —OCO(optionally substituted        heterocyclyl), heterocyclyl, heteroaryl, or aryl    -   R^(2a) and R^(3a) is each independently selected from halogen,        —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,        —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy, —C₃-C₆        cycloalkyl, —S(C₁-C₆ alkyl), —SO(C₁-C₆ alkyl), —SO₂(C₁-C₆        alkyl), —COR^(g), —NR^(a)R^(b), —OCOR⁹, —OCOOR^(g),        —OCO(optionally substituted heterocyclyl), —NR^(a)COOR^(g),        —NR^(a)CONR^(a)R^(b), —CONR^(a)R^(b), —CONR^(c)R^(d),        heterocyclyl, heteroaryl, or aryl;    -   R^(a) and R^(b) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆        alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f),        —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃        alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f),        —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl),        —CO(CH₂)_(n)(cycloalkyl), —CO(CH₂)_(n)(optionally substituted        aryl), —CO(CH₂)_(n)(optionally substituted heterocyclyl),        —CO(CH₂)_(n)(optionally substituted heteroaryl);    -   R^(c) and R^(d) together with the nitrogen atom to which it is        attached to form an optionally substituted ring, which can be        monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring        atom can contain up to 3 heteroatoms selected from N, O, or S;    -   R^(e) and R^(f) are each independently selected from H, —C₁-C₆        alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH;    -   R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl,        phenyl, or benzyl;    -   R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃        alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b); and    -   X is, O or NH, or CH₂ optionally substituted with —C₁-C₆ alkyl,        —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,        —C₁-C₆ haloalkoxy, o-C₃-C₆ cycloalkyl, —COR^(g), —NR^(a)R^(b),        or —OCOR⁹.

In one embodiment of the compounds of formula (VIII), R₂ is phenyloptionally substituted with one or more with one or more R^(2a).

In one embodiment of the compounds of formula (VIII), at least oneR^(2a) is halogen, —CN or —NO₂.

In one embodiment of the compounds of formula (VIII), at least oneR^(2a) is —NO₂.

In one embodiment of the compounds of formula (VIII), R₁ is —C₁-C₆alkyl.

In one embodiment of the compounds of formula (VIII), R₃ is aryl orheteroaryl, optionally substituted with one or more halogen, —OH, —CN,—NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl,—C₁-C₆ alkoxy, or —C₁-C₆ haloalkoxy. In one embodiment, R₃ is phenyl orthienyl optionally substituted with one or more halogen, —OH, —CN, —NO₂,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆alkoxy, or —C₁-C₆ haloalkoxy. In one embodiment, R₃ is phenyl or thienyloptionally substituted with one or more halogen or —OCH₃. In oneembodiment, R₃ is phenyl substituted with Cl.

In one embodiment of the compounds of formula (VIII), X is CH₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is —C₁-C₆ alkyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R₃ is aryl or heteroaryl, optionally substituted with one or        more halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, or —C₁-C₆        haloalkoxy; and    -   X is CH₂.

In one embodiment of the compounds of formula (VIII), R^(2a) is halogen,—CN or —NO₂.

In one embodiment of the compounds of formula (VIII), at least oneR^(2a) is —NO₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is —C₁-C₆ alkyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R₃ is phenyl or thienyl optionally substituted with one or more        halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, or —C₁-C₆ haloalkoxy;        and    -   X is CH₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is —C₁-C₆ alkyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R₃ is phenyl or thienyl optionally substituted with one or more        halogen or —OCH₃; and    -   X is CH₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is —C₁-C₆ alkyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R₃ is phenyl substituted with Cl; and    -   X is CH₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is —C₁-C₆ alkyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R^(2a) is halogen, —CN or —NO₂ and R₃ is phenyl or thienyl        optionally substituted with one or more halogen or —OCH₃;    -   R₃ is aryl or heteroaryl, optionally substituted with one or        more halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, or —C₁-C₆        haloalkoxy; and    -   X is CH₂.

In one embodiment of the compounds of formula (VIII),

-   -   R₁ is isopropyl;    -   R₂ is phenyl optionally substituted with one or more with one or        more R^(2a),    -   R₃ is aryl or heteroaryl, optionally substituted with one or        more halogen, —OH, —CN, —NO₂, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, or —C₁-C₆        haloalkoxy; and    -   X is CH₂.

In one aspect, the present disclosure relates to pharmaceuticalcompositions comprising a compound of formula (A) or (I)-(VIII) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.

In one aspect, the present disclosure relates to methods of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by orexin receptor activity, wherein the disease,disorder, or medical condition is a disorder of the sleep-wake cycle,insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleepdisorder secondary to neurological disorders, mania, depression, manicdepression, schizophrenia, a pain syndromes, fibromyalgia, neuropathicpain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety,delirium, dementia, overweight, obesity or a condition related tooverweight or obesity, insulin resistance, type II diabetes,hyperlipidemia, gallstones, angina, hypertension, breathlessness,tachycardia, infertility, sleep apnea, back and joint pain, varicoseveins, osteoarthritis, hypertension, tachycardia, arrhythmias, anginapectoris, acute heart failure, ulcers, irritable bowel syndrome,diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panicdisorders, attention deficit disorders, cognitive deficiencies, orsubstance abuse, comprising administering to the subject an effectiveamount of a compound of formula (A) or (I)-(VIII) or a pharmaceuticallyacceptable salt thereof.

In one aspect, the present disclosure relates to methods for thetreatment of one or more sleep disorders, comprising administering tothe subject an effective amount of a compound of formula (A) or(I)-(VIII) or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure relates to methods of promoting orenhancing wakefulness, anti-obesity, or recovery from general anesthesiaor jet lag in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of formula (A) or (I)-(VIII)or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure relates to methods of increasingresistance to diet-induced accumulation of body fat, comprisingadministering to the subject an effective amount of a compound offormula (A) or (I)-(VIII) or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure relates to methods of shorteningrecovery period from general anesthesia or jet lag, comprisingadministering to the subject an effective amount of a compound offormula (A) or (I)-(VIII) or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure relates to methods of treatingnarcolepsy in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of formula (A) or (I)-(VIII)or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure relates to methods for agonizing atype-2 orexin receptor (OX2R), comprising contacting the OX2R with acompound of formula (A) or (I)-(VIII) or a pharmaceutically acceptablesalt thereof.

In one embodiment of the methods of agonizing OX2R, the contacting is ina cell.

In one embodiment of any of the methods as disclosed herein, thecompound is administered to the subject regularly and/or chronically.

In one embodiment of any of the methods as disclosed herein, thecompound is administered to the subject orally.

In particular embodiments, the invention includes the compounds, genera,and subgenera in Tables 1-14.

Other aspects and embodiments of the invention are embodied in thefollowing additional numbered Embodiments:

1. A OX2R agonist compound of formula I:

wherein:

Ar1 and Ar2 are independently optionally substituted C5-C10 aryl orheteroaryl (having from one to three heteroatoms selected from nitrogen,oxygen and sulfur);

Ar1 and Ar2 are independently optionally substituted phenyl;

Ar1 and Ar2 are independently phenyl, optionally substituted with halo,cyano, optionally fluorinated C1-C4 alkyl, or

Ar1 and Ar2 are 4-methyl phenyl;

R1 is optionally substituted, optionally hetero-, optionally cyclicC1-C10 hydrocarbyl, or optionally substituted heteroatom;

R1 is amide, amine, hydroxyl, hydrocarbyloxy;

R1 is OR, NRR, NHCOR, CONRR, wherein each R is independently H,optionally fluorinated C1-C4 alkyl, etc.; or

R1 is OH, OMe, OMeOR, NRR, CONRR, NHC(O)R, wherein each R isindependently H, optionally fluorinated C1-C4 alkyl, etc.;

R2 together with its double bond is carbonyl or imine,

R2 is O or NR, wherein R is H, Me, tert-butyloxycarbonyl (Boc),optionally fluorinated C1-C4 alkyl, C1-C4 alkyloxy, C1-C4alkyloxycarbonyl, etc.; or

R2 is O or NH or NMe;

R3, R4 and R5 are independently H or optionally fluorinated C1-C4 alkyl(e.g. Me, Et, CF3, isopropyl, cyclopropyl, cyclobutyl), cyano, nitro,carboxyl, acetyl;

each R6 is independently optionally fluorinated C1-C4 alkyl (e.g. Me,Et, CF3, isopropyl, cyclopropyl, cyclobutyl), cyano, nitro, carboxyl,acetyl; or

each R6 is independently halide, Me, CF3, CN, SMe, t-butyl, OCF3, OMe;

n is an integer 0-4; and

Y1 and Y2 are independently N or CR, where R is H or R⁶; or

a stereoisomer, hydrate or salt thereof.

2. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are independently optionally substituted phenyl;

R1 is amide, amine, hydroxyl, hydrocarbyloxy; and

R2 together with its double bond is carbonyl or imine;

Y1 and Y2 are independently N or CH, or

a stereoisomer, hydrate or salt thereof.

3. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are independently phenyl, optionally substituted with halo,cyano, optionally fluorinated C1-C4 alkyl;

R1 is amide, amine, hydroxyl, hydrocarbyloxy; and

R2 together with its double bond is carbonyl or imine;

Y1 and Y2 are independently N or CH, or a stereoisomer, hydrate or saltthereof.

4. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are 4-methyl phenyl;

R1 is OH, OMe, OMeOR, NRR, CONRR, NHC(O)R, wherein each R isindependently H, optionally fluorinated C1-C4 alkyl;

R2 is O or NR, wherein R is H, Me, tert-butyloxycarbonyl (Boc),optionally fluorinated C1-C4 alkyl, C1-C4 alkyloxy, C1-C4alkyloxycarbonyl;

R3, R4 and R5 are independently H or optionally fluorinated C1-C4 Me;

Y1 and Y2 are independently N or CH, or a stereoisomer, hydrate or saltthereof.

5. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are 4-methyl phenyl;

R1 is OH, OMe, NHMe, NMe2, NHSO₂R16 or NHCOR16, where R16 is Me, CF3,OH, OMe, OEt, ethyl, phenyl, cyclo propyl, isopropyl, benzyl, NH2, NRR,CONR2 (reverse amides) or NHC(O)R (amides),

R2 is O or NH or NMe;

R3, R4 and R5 are independently H or optionally fluorinated C1-C4 Me;

n is 0;

Y1 and Y2 are independently N or CH, or

a stereoisomer, hydrate or salt thereof.

6. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are independently 4-methyl phenyl;

R1 is OH, OMe, NHMe, NMe2, NHSO2R16 or NHCOR16, where R16 is Me, CF3,OH, OMe, OEt, ethyl, phenyl, cyclo propyl, isopropyl, benzyl, NH2, NRR,CONR2 (reverse amides) or NHC(O)R (amides);

R2 is O or NH;

R3, R4 and R5 are independently H or optionally fluorinated C1-C4 Me;

-   -   n is 0;

Y1 and Y2 are N and CH, or

a stereoisomer, hydrate or salt thereof.

7. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are independently optionally substituted phenyl, and

R1 is OH, OMe, NHMe, NMe₂, NHSO₂R16 or NHCOR16, where R16 is Me, CF₃,OH, OMe, OEt, ethyl, phenyl, cyclo propyl, isopropyl, benzyl, NH2, NRR,CONR2 (reverse amides) or NHC(O)R (amides);

R1 is OH, OMe, OMeOR, NRR, CONRR, NHC(O)R, wherein each R isindependently H, optionally fluorinated C1-C4 alkyl, etc.;

R2 is O, NH or NMe;

R3 is H;

R4 is H or Me; and

R5 is H or Me,

n is 0;

Y1 and Y2 are N and CH, or

a stereoisomer, hydrate or salt thereof.

8. The compound of Embodiment 1 wherein:

Ar1 and Ar2 are 4-methyl phenyl;

R1 is OMe;

R2 is O or NH;

R3 is H;

R4 is H or Me;

R5 is H or Me;

n is 0;

Y1 and Y2 are N and CH, or

a stereoisomer, hydrate or salt thereof.

9. The compound of Embodiments 1, 2, 3, 4, 5, 6, 7 or 8 comprising allcombinations wherein:

R is independently H, or optionally substituted, optionally hetero-,optionally cyclic C1-C10 hydrocarbyl, or optionally substitutedheteroatom;

substituents are optionally substituted, optionally hetero-, optionallycyclic C1-C10 hydrocarbyl, or optionally substituted heteroatom,

the hydrocarbyl is alkyl, akenyl, alkynyl, carbonyl, carbonothioyl,carbonothioyl, cyano, oxime or imine;

the carbonyl is ester, carboxyl, ketone, aldehyde, amide, acyl halide,acid anhydride or imide; and/or

the optionally substituted heteroatom is halide, amine, nitro, nitroso,nitrile, cyanato, isocyanato, isocyano, oxo, hydroxyl, hydrocarbyloxy,nitrate, nitrosoxy, azo, azide, thiol, sulfide, sulfoxide, sulfonyl,sulfinic acids, sulfonic acid, thiocyanate, phosphate, phosphono orborono, or

a stereoisomer, hydrate or salt thereof.

10. The compound of Embodiment 1 comprising a structure of Table 1,Table 2 or Table 3.

11. A pharmaceutical composition comprising the compound of any ofEmbodiments 1-10,

a stereoisomer, hydrate or salt thereof, in effective unit dosage thatpromotes wakefulness, anti-obesity, or recovery from general anesthesiaor jet lag.

12. A pharmaceutical composition of Embodiment 11 coformulated with adifferent compound which promotes wakefulness, anti-obesity, or recoveryfrom general anesthesia or jet lag.

13. A pharmaceutical composition of Embodiment 11 formulated in unitdosages separately packaged in a multipack adapted for sequential use.

14. A method for agonizing a type-2 orexin receptor (OX2R) in a celldetermined to be in need thereof, comprising the steps of:

contacting the receptor with the compound of any of Embodiments 1-10, ora stereoisomer, hydrate or salt thereof, or prodrug thereof; andoptionally,

detecting a resultant agonizing or activation of the receptor.

15. The method of Embodiment 14 wherein:

the cell is in situ in a subject, the compound or stereoisomer, hydrateor salt thereof, or prodrug thereof is orally administered to thesubject, and the agonizing or activation is inferred from enhancedwakefulness or increased resistance to diet-induced accumulation of bodyfat, or abbreviated recovery from general anesthesia or jet lag;

the method comprises administering to the subject the compound orstereoisomer, hydrate or salt thereof, or prodrug thereof regularly andchronically;

the method comprises comprising administering to the subject thecompound or stereoisomer, hydrate or salt thereof, or prodrug thereof inconjunction with an effective amount of a different compound whichpromotes wakefulness, anti-obesity, or recovery from general anesthesiaor jet lag; or

the method comprises comprising administering to the subject thecompound or stereoisomer, hydrate or salt thereof, or prodrug thereof inunit dosage form, and comprising the antecedent step of removing acapsule or tablet comprising the unit dosage form from a multipackadapted for sequential use.

The disclosed orally active, blood-brain barrier permeable,small-molecule OX2R agonists provide effective physiological agonistsand treatments for narcolepsy.

The disclosed OX2R agonists may also be used to promote or maintainproper wakefulness, and to treat medical conditions accompanying daytimesleepiness, such as nighttime insomnia, and depression with hypersomnia.

The disclosed OX2R agonists also provide treatments of obesity andassociated metabolic syndrome, and may also be used to facilitate orexpedite recovery from general anesthesia.

In particular embodiments, the method provides a therapy or prophylaxis,wherein the cell is in situ in a subject, the OX2R agonist is orallyadministered to the subject, and the agonizing or activation is inferredfrom a resultant physiological effect, such as enhanced wakefulness orincreased resistance to diet-induced accumulation of body fat, orenhanced recovery from general anesthesia or jet lag. In more specificembodiments, this in situ protocol comprises (i) administering to thesubject the OX2R agonist regularly and chronically; (ii) administeringto the subject the OX2R agonist in conjunction with an effective amountof a different compound which promotes wakefulness, anti-obesity, orrecovery from general anesthesia or jet lag; or (iii) administering tothe subject the OX2R agonist in unit dosage form, and comprising theantecedent step of removing a capsule or tablet comprising the unitdosage form from a multipack adapted for sequential use.

The invention also provides pharmaceutical compositions comprising asubject OX2R agonist, particularly as coformulated with a differentcompound which promotes wakefulness, anti-obesity, or recovery fromgeneral anesthesia or jet lag, and/or formulated in unit dosagesseparately packaged in a multipack adapted for sequential use.

pharmaceutical composition comprising a subject OX2R agonist, includingall embodiments described herein, coformulated with a different compoundwhich promotes wakefulness, anti-obesity, or recovery from generalanesthesia or jet lag

A pharmaceutical composition comprising a subject OX2R agonist,including all embodiments described herein, formulated in unit dosagesseparately packaged in a multipack adapted for sequential use.

A method for agonizing a type-2 orexin receptor (OX2R) in a celldetermined to be in need thereof, comprising the steps of:

contacting the receptor with a disclosed OX2R agonist, or apharmaceutically acceptable salt thereof, or prodrug thereof; andoptionally, detecting a resultant agonizing or activation of thereceptor.

A method herein, wherein the cell is in situ in a subject, the OX2Ragonist is orally administered to the subject, and the agonizing oractivation is inferred from enhanced wakefulness or increased resistanceto diet-induced accumulation of body fat, or abbreviated recovery fromgeneral anesthesia or jet lag.

A method herein comprising administering to the subject the OX2R agonistregularly and chronically.

A method herein comprising administering to the subject the OX2R agonistin conjunction with an effective amount of a different compound whichpromotes wakefulness, anti-obesity, or recovery from general anesthesiaor jet lag.

A method herein comprising administering to the subject the OX2R agonistin unit dosage form, and comprising the antecedent step of removing acapsule or tablet comprising the unit dosage form from a multipackadapted for sequential use.

The invention includes all combinations of recited particularembodiments as if each combination had been laboriously recited.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-55 illustrate the IP accumulation assays for the compoundsdisclosed herein. Structures for these compounds can be found in Table1.

FIG. 56 illustrates the structure of MKG-25.

FIG. 57 illustrates the IP accumulation results of ARN-245 and WW-6-61,showing ether series: increased potency, better BBB.

FIG. 58 illustrates the orexin neuropeptide system.

FIG. 59 illustrates a high-throughput screening assay.

FIG. 60 illustrates the validation of the reporter cell lines using thehigh-throughput screening assay: CHO cells (NFAT-luciferase)co-transfected with OX1R, OX2R, or GRPR: OXA (M).

FIG. 61 illustrates the validation of the reporter cell lines using thehigh-throughput screening assay: CHO cells (NFAT-luciferase)co-transfected with OX1R, OX2R, or GRPR: GRM (M).

FIG. 62 illustrates four hit families identified through thehigh-throughput screening assay.

FIG. 63 illustrates the activity of the four hits in various assays.

FIG. 64 illustrates an example of Chemotype 1 and its activity; 1A:X=Me; EC₅₀˜300 nM.

FIG. 65 illustrates the stability of a compound of Chemotype 1.

FIG. 66 illustrates the results of SAR analysis of certain compounds ofChemotype 1.

FIG. 67 summaries the tested activity of certain compounds of Chemotype1.

FIGS. 68-72 illustrate compounds of Chemotype 2.

FIGS. 73 and 74 illustrate compounds of Chemotype 4.

FIGS. 75-77 illustrate compounds of Chemotype 3.

FIG. 78 illustrates the IP assay for OX₂R-expressing HEK cells.

FIG. 79 shows results of the initial SAR studies.

FIGS. 80-83 summarize SAR results for Chemotype 3.

FIG. 84-85 illustrate additional compounds of Chemotype 3

FIGS. 86 and 87 show additional chemotypes identified by the primaryHTS.

DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION

All publications, patents and patent applications, including anydrawings and appendices therein are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent or patent application, drawing, or appendix wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes.

Definitions

While the following terms are believed to be well understood by one ofordinary skill in the art, the following definitions are set forth tofacilitate explanation of the presently disclosed subject matter.

Throughout the present specification, the terms “about” and/or“approximately” may be used in conjunction with numerical values and/orranges. The term “about” is understood to mean those values near to arecited value. Furthermore, the phrases “less than about [a value]” or“greater than about [a value]” should be understood in view of thedefinition of the term “about” provided herein. The terms “about” and“approximately” may be used interchangeably.

Throughout the present specification, numerical ranges are provided forcertain quantities. It is to be understood that these ranges compriseall subranges therein. Thus, the range “from 50 to 80” includes allpossible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70,etc.). Furthermore, all values within a given range may be an endpointfor the range encompassed thereby (e.g., the range 50-80 includes theranges with endpoints such as 55-80, 50-75, etc.).

The term “a” or “an” refers to one or more of that entity; for example,“an orexin receptor agonist” refers to one or more orexin receptoranoists or at least one orexin receptor agonist. As such, the terms “a”(or “an”), “one or more” and “at least one” are used interchangeablyherein. In addition, reference to “an inhibitor” by the indefinitearticle “a” or “an” does not exclude the possibility that more than oneof the inhibitors is present, unless the context clearly requires thatthere is one and only one of the inhibitors.

As used herein, the verb “comprise” as is used in this description andin the claims and its conjugations are used in its non-limiting sense tomean that items following the word are included, but items notspecifically mentioned are not excluded. The present invention maysuitably “comprise”, “consist of”, or “consist essentially of”, thesteps, elements, and/or reagents described in the claims.

The term “alkyl” refers to a fully saturated, hydrocarbon group selectedfrom linear and branched saturated hydrocarbon groups of 1-18 carbonatoms (C₁-C₁₈ alkyl), or 1-12 carbon atoms (C₁-C₁₂ alkyl), or 1-6 carbonatoms (C₁-C₆ alkyl), which is attached to the rest of the molecule by asingle bond. Non-limiting examples of the alkyl group include methyl,ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”),1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”),1-methylpropyl or s-butyl (“s-Bu”), and 1,1-dimethylethyl or t-butyl(“t-Bu”). Other non-limiting examples of the alkyl group include1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and3,3-dimethyl-2-butyl groups. Unless stated otherwise specifically in thespecification, an alkyl group can be optionally substituted.

The term “haloalkyl” refers to an alkyl group which is substituted withat least one halogen. Non-limiting examples of haloalkyl includes, —CF₃,—CHF₂, —CH₂F, —CCF₂, —CFCl₂, —CCl₃, CHCl₂, —CH₂Cl, —CBr₃, CHBr₂, —CH₂Br,—Cl₃, CHI₂, —CH₂I, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CHFCF₃, —CF₂CF₃,—CH₂CCl₃, —CH₂CHCl₂, —CH₂CH₂Cl, —CHClCCl₃, —CCl₂CCl₃, —CH₂CH₂CF₃,—CH₂CH₂CHF₂, —CH₂CH₂CH₂F, —CF₂CF₂CF₃.

“Alkylene” or “alkylene chain” refers to a fully saturated, straight orbranched divalent hydrocarbon chain radical, and having from one totwelve carbon atoms. Non-limiting examples of C₁-C₁₂ alkylene includemethylene, ethylene, propylene, n-butylene, ethenylene, propenylene,n-butenylene, propynylene, n-butynylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupcan be through one carbon or any two carbons within the chain. Unlessstated otherwise specifically in the specification, an alkylene chaincan be optionally substituted.

The term “alkenyl” refers to a hydrocarbon group selected from linearand branched hydrocarbon groups comprising at least one C═C double bondand of 2-18 carbon atoms (C₂-C₁₈ alkenyl), or 2-12 carbon atoms (C₂-C₁₂alkenyl), or 2-6 carbon atoms (C₂-C₆ alkenyl). Non-limiting examples ofthe alkenyl group includes ethenyl or vinyl, prop-1-enyl, prop-2-enyl,2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl, and hexa-1,3-dienylgroups. Other non-limitingexamples of alkenyl groups include, 1-heptenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl,4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl,3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl,1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl,7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl,4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl,9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl,4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl,9-dodecenyl, 10-dodecenyl, and 11-dodecenyl Unless stated otherwisespecifically in the specification, an alkenyl group can be optionallysubstituted.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon double bonds. Non-limitingexamples of C₂-C₁₂ alkenylene include ethene, propene, butene, and thelike. The alkenylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkenylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkenylene chain can be optionally substituted.

The term “alkynyl” refers to a hydrocarbon group selected from linearand branched hydrocarbon group, comprising at least one C≡C triple bondand of 2-18, or 2-12, or 2-6 carbon atoms. Examples of the alkynyl groupinclude ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl,2-butynyl, and 3-butynyl groups. Unless stated otherwise specifically inthe specification, an alkenyl group can be optionally substituted.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain radical, having from two to twelve carbonatoms, and having one or more carbon-carbon triple bonds. Non-limitingexamples of C₂-C₁₂ alkynylene include ethynylene, propargylene and thelike. The alkynylene chain is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkynylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain. Unless stated otherwise specifically in thespecification, an alkynylene chain can be optionally substituted.

The term “lower alkyl” means alkyl groups of 1-8 carbon atoms (C₁-C₈alkyl), 1-6 (C₁-C₆ alkyl), or 1-4 carbon atoms (C₁-C₄ alkyl). The term“lower alkenyl” or “lower alkynyl” means alkenyl or alkynyl groups of2-8, 2-6 or 2-4 carbon atoms (e.g., C₂-C₈ alkenyl, C₂-C₆ alkenyl, C₂-C₄alkenyl, C₂-C₈ alkynyl, C₂-C₆ alkynyl, C₂-C₄ alkynyl).

The term “cycloalkyl” refers to a monocyclic and polycyclic (e.g.,bicyclic and tricyclic) hydrocarbon group which is saturated orpartially unsaturated (non-aromatic). Cycloalkyl group can have fromthree to twenty carbon atoms, which can be fused or bridged. Forexample, the cycloalkyl group may be of 3-12, or 3-8, or 3-6 carbonatoms. Even further for example, the cycloalkyl group may be amonocyclic group of 3-12, or 3-8, or 3-6 carbon atoms. Examples of themonocyclic cycloalkyl group include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, and cyclododecyl groups. Examples of the bicycliccycloalkyl groups include those having 7-12 ring atoms arranged as abicycle ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ringsystems, or as a bridged bicyclic ring selected frombicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.The ring may be saturated or have at least one double bond (i.e.partially unsaturated), but is not fully conjugated, and is notaromatic, as aromatic is defined herein. Unless stated otherwisespecifically in the specification, cycloalkyl group can be optionallysubstituted.

Partially unsaturated cycloalkyl group having at least one carbon-carbondouble bond can be separately referred to as “cycloalkenyl”. Partiallyunsaturated cycloalkyl group having at least one carbon-carbon triplebond can be separately referred to as “cycloalkynyl”.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl, alkenyl or alknyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkoxy group can be optionally substituted.

“Haloalkoxy” refers to a radical of the formula —OR_(a) where R_(a) isan haloalkyl, haloalkenyl or haloalknyl radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkoxy group can be optionallysubstituted.

The term “Aryl” herein refers to a group selected from: 5- and6-membered carbocyclic aromatic rings, for example, phenyl; bicyclicring systems such as 7-12 membered bicyclic ring systems wherein atleast one ring is carbocyclic and aromatic, selected, for example, fromnaphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ringsystems such as 10-15 membered tricyclic ring systems wherein at leastone ring is carbocyclic and aromatic, for example, fluorene. As usedherein, a bicyclic or tricyclic aryl group comprises at least onearomatic group and includes fused and bridged rings. Unless statedotherwise specifically in the specification, an aryl group can beoptionally substituted.

For example, the aryl group is selected from 5- and 6-memberedcarbocyclic aromatic rings fused to a 5- to 7-membered cycloalkyl orheterocyclic ring optionally comprising at least one heteroatom selectedfrom N, O, and S, provided that the point of attachment is at thecarbocyclic aromatic ring when the carbocyclic aromatic ring is fusedwith a heterocyclic ring, and the point of attachment can be at thecarbocyclic aromatic ring or at the cycloalkyl group when thecarbocyclic aromatic ring is fused with a cycloalkyl group. Bivalentradicals formed from substituted benzene derivatives and having the freevalences at ring atoms are named as substituted phenylene radicals.Bivalent radicals derived from univalent polycyclic hydrocarbon radicalswhose names end in “-yl” by removal of one hydrogen atom from the carbonatom with the free valence are named by adding “-idene” to the name ofthe corresponding univalent radical, e.g., a naphthyl group with twopoints of attachment is termed naphthylidene. Aryl, however, does notencompass or overlap with heteroaryl, separately defined below. Hence,if one or more carbocyclic aromatic rings are fused with a heterocyclicaromatic ring, the resulting ring system is heteroaryl, not aryl, asdefined herein.

“Arylene” refers to a divalent aryl group.

The term “halogen” or “halo” refers to F, Cl, Br or I.

The term “heteroalkyl” refers to alkyl comprising at least oneheteroatom.

The term “heteroaryl” refers to a group selected from: 5- to 7-memberedaromatic, monocyclic rings comprising 1, 2, 3 or 4 heteroatoms selectedfrom N, O, and S, with the remaining ring atoms being carbon; 8- to12-membered bicyclic rings comprising 1, 2, 3 or 4 heteroatoms, selectedfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one ring is aromatic and at least one heteroatom is present inthe aromatic ring; and 11- to 14-membered tricyclic rings comprising 1,2, 3 or 4 heteroatoms, selected from N, O, and S, with the remainingring atoms being carbon and wherein at least one ring is aromatic and atleast one heteroatom is present in an aromatic ring. As used herein, abicyclic or tricyclic heteroaryl group comprises at least one aromaticgroup and includes fused and bridged rings. Unless stated otherwisespecifically in the specification, a heteroaryl group can be optionallysubstituted.

For example, the heteroaryl group includes a 5- to 7-memberedheterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.For such fused, bicyclic heteroaryl ring systems wherein only one of therings comprises at least one heteroatom, the point of attachment may beat the heteroaromatic ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of the heteroaryl group include, but are not limited to, (asnumbered from the linkage position assigned priority 1) pyridyl (such as2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl,2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl,isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl,thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl,indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl,pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl,pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl),pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl(such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl,1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl,1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl,1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, benzothiazolyl (such asbenzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and5,6,7,8-tetrahydroisoquinoline.

“Heteroarylene” refers to a divalent heteroaryl group.

The term “heterocyclic” or “heterocycle” or “heterocyclyl” refers to aring selected from 4- to 12-membered monocyclic, bicyclic and tricyclic,saturated and partially unsaturated rings comprising at least one carbonatoms in addition to 1, 2, 3 or 4 heteroatoms, selected from oxygen,sulfur, and nitrogen. “Heterocycle” also refers to a 5- to 7-memberedheterocyclic ring comprising at least one heteroatom selected from N, O,and S, fused with 5-, 6-, and/or 7-membered cycloalkyl, carbocyclicaromatic or heteroaromatic ring, provided that the point of attachmentis at the heterocyclic ring when the heterocyclic ring is fused with acarbocyclic aromatic or a heteroaromatic ring, and that the point ofattachment can be at the cycloalkyl or heterocyclic ring when theheterocyclic ring is fused with cycloalkyl. “Heterocycle” also refers toan aliphatic spirocyclic ring comprising at least one heteroatomselected from N, O, and S, provided that the point of attachment is atthe heterocyclic ring. The rings may be saturated or have at least onedouble bond (i.e. partially unsaturated). The heterocycle may besubstituted with oxo. The point of the attachment may be carbon orheteroatom in the heterocyclic ring. A heterocyle is not a heteroaryl asdefined herein. Unless stated otherwise specifically in thespecification, a heterocyclic group can be optionally substituted.

Examples of the heterocycle include, but not limited to, (as numberedfrom the linkage position assigned priority 1) 1-pyrrolidinyl,2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl,2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl,azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl,dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl,piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl,thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepane1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl,dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl,1,1-dioxo-thiomorpholinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. Substitutedheterocycle also includes ring systems substituted with one or more oxomoieties, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.

Unless otherwise specified in the specification, substituents areselected from: halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR′, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)₂═NH, —NH—C(NH₂)═NR′, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R,—CN and —NO₂, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to three, withthose groups having zero, one or two substituents being particularlypreferred. R′, R″ and R′ each independently refer to hydrogen,unsubstituted (C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, or aryl-(C₁-C₄)alkyl groups. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. Hence, —NR′R″includes 1-pyrrolidinyl and 4-morpholinyl, “alkyl” includes groups suchas trihaloalkyl (e.g., —CF₃ and —CH₂CF₃), and when the aryl group is1,2,3,4-tetrahydronaphthalene, it may be substituted with a substitutedor unsubstituted (C₃-C₇)spirocycloalkyl group. The(C₃-C₇)spirocycloalkyl group may be substituted in the same manner asdefined herein for “cycloalkyl”.

Preferred substituents are selected from: halogen, —R′, —OR′, ═O,—NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″, —S(O)R′, —SO₂R′,—SO₂NR′R″, —NR″SO₂R, —CN and —NO₂, perfluoro(C1-C4)alkoxy andperfluoro(C1-C4)alkyl, where R′ and R″ are as defined above.

The term “fused ring” herein refers to a polycyclic ring system, e.g., abicyclic or tricyclic ring system, in which two rings share only tworing atoms and one bond in common. Examples of fused rings may comprisea fused bicyclic cycloalkyl ring such as those having from 7 to 12 ringatoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5],[5,6] and [6,6] ring systems as mentioned above; a fused bicylclic arylring such as 7 to 12 membered bicyclic aryl ring systems as mentionedabove, a fused tricyclic aryl ring such as 10 to 15 membered tricyclicaryl ring systems mentioned above; a fused bicyclic heteroaryl ring suchas 8- to 12-membered bicyclic heteroaryl rings as mentioned above, afused tricyclic heteroaryl ring such as 11- to 14-membered tricyclicheteroaryl rings as mentioned above; and a fused bicyclic or tricyclicheterocyclyl ring as mentioned above.

The compounds may contain an asymmetric center and may thus exist asenantiomers. Where the compounds possess two or more asymmetric centers,they may additionally exist as diastereomers. Enantiomers anddiastereomers fall within the broader class of stereoisomers. All suchpossible stereoisomers as substantially pure resolved enantiomers,racemic mixtures thereof, as well as mixtures of diastereomers areintended to be included. All stereoisomers of the compounds and/orpharmaceutically acceptable salts thereof are intended to be included.Unless specifically mentioned otherwise, reference to one isomer appliesto any of the possible isomers. Whenever the isomeric composition isunspecified, all possible isomers are included.

The term “substantially pure” means that the target stereoisomercontains no more than 35%, such as no more than 30%, further such as nomore than 25%, even further such as no more than 20%, by weight of anyother stereoisomer(s). In some embodiments, the term “substantiallypure” means that the target stereoisomer contains no more than 10%, forexample, no more than 5%, such as no more than 1%, by weight of anyother stereoisomer(s).

When compounds contain olefin double bonds, unless specified otherwise,such double bonds are meant to include both E and Z geometric isomers.

Some of the compounds may exist with different points of attachment ofhydrogen, referred to as tautomers. For example, compounds includingcarbonyl —CH₂C(O)— groups (keto forms) may undergo tautomerism to formhydroxyl —CH═C(OH)— groups (enol forms). Both keto and enol forms,individually as well as mixtures thereof, are also intended to beincluded where applicable.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may beobtained by resolution of the racemic mixture using a method such asformation of diastereomers using optically active resolving agents(Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al.“Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., Ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, selected, for example, from hydrochlorates,phosphates, diphosphates, hydrobromates, sulfates, sulfinates, andnitrates; as well as salts with organic acids, selected, for example,from malates, maleates, fumarates, tartrates, succinates, citrates,lactates, methanesulfonates, p-toluenesulfonates,2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoatessuch as acetate, and salts with HOOC—(CH₂)n-COOH, wherein n is selectedfrom 0 to 4. Similarly, examples of pharmaceutically acceptable cationsinclude, but are not limited to, sodium, potassium, calcium, aluminum,lithium, and ammonium.

In addition, if a compound is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt, such as apharmaceutically acceptable addition salt, may be produced by dissolvingthe free base in a suitable organic solvent and treating the solutionwith an acid, in accordance with conventional procedures for preparingacid addition salts from base compounds. Those skilled in the art willrecognize various synthetic methodologies that may be used without undueexperimentation to prepare non-toxic pharmaceutically acceptableaddition salts.

“Treating,” “treat,” or “treatment” refers to administering at least onecompound and/or at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof to a subject in recognized needthereof. The term “treating” means one or more of relieving,alleviating, delaying, reducing, improving, or managing at least onesymptom of a condition in a subject. The term “treating” may also meanone or more of arresting, delaying the onset (i.e., the period prior toclinical manifestation of the condition) or reducing the risk ofdeveloping or worsening a condition.

An “effective amount” refers to an amount of at least one compoundand/or at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof effective to “treat” a diseaseor disorder in a subject, and that will elicit, to some significantextent, the biological or medical response of a tissue, system, animalor human that is being sought, such as when administered, is sufficientto prevent development of, or alleviate to some extent, one or more ofthe symptoms of the condition or disorder being treated. Thetherapeutically effective amount will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

The term “at least one substituent” includes, for example, from 1 to 4,such as from 1 to 3, further as 1 or 2, substituents. For example, “atleast one substituent R¹⁶” herein includes from 1 to 4, such as from 1to 3, further as 1 or 2, substituents selected from the list of R¹⁶ asdescribed herein.

The subject compounds and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof may be employed alone or in combination with atleast one other therapeutic agent for treatment. In some embodiments,the compounds, stereoisomers thereof, and pharmaceutically acceptablesalts thereof can be used in combination with at least one additionaltherapeutic agent. The compound and/or one pharmaceutically acceptablesalt disclosed herein may be administered with the at least one othertherapeutic agent in a single dosage form or as a separate dosage form.When administered as a separate dosage form, the at least one othertherapeutic agent may be administered prior to, at the same time as, orfollowing administration of the compound and/or one pharmaceuticallyacceptable salt disclosed herein.

Also provided is a composition comprising a subject compound andstereoisomers thereof, and pharmaceutically acceptable salts thereof,and at least one pharmaceutically acceptable carrier.

The composition comprising a subject compound and stereoisomers thereof,and pharmaceutically acceptable salts thereof can be administered invarious known manners, such as orally, topically, rectally,parenterally, by inhalation spray, or via an implanted reservoir,although the most suitable route in any given case will depend on theparticular host, and nature and severity of the conditions for which theactive ingredient is being administered. The term “parenteral” as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques. The compositions disclosed herein may beconveniently presented in unit dosage form and prepared by any of themethods well known in the art.

The subject compounds and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof can be administered orally in solid dosageforms, such as capsules, tablets, troches, dragées, granules andpowders, or in liquid dosage forms, such as elixirs, syrups, emulsions,dispersions, and suspensions. The subject compounds and stereoisomersthereof, and pharmaceutically acceptable salts thereof disclosed hereincan also be administered parenterally, in sterile liquid dosage forms,such as dispersions, suspensions or solutions. Other dosages forms thatcan also be used to administer the subject compounds and stereoisomersthereof, and pharmaceutically acceptable salts thereof disclosed hereinas an ointment, cream, drops, transdermal patch or powder for topicaladministration, as an ophthalmic solution or suspension formation, i.e.,eye drops, for ocular administration, as an aerosol spray or powdercomposition for inhalation or intranasal administration, or as a cream,ointment, spray or suppository for rectal or vaginal administration.

Gelatin capsules containing the compound and/or the at least onepharmaceutically acceptable salt thereof disclosed herein and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like, can also be used. Similar diluentscan be used to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can further comprise atleast one agent selected from coloring and flavoring agents to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene gycols can be examples of suitable carriers for parenteralsolutions. Solutions for parenteral administration may comprise a watersoluble salt of the at least one compound describe herein, at least onesuitable stabilizing agent, and if necessary, at least one buffersubstance. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, can be examples ofsuitable stabilizing agents. Citric acid and its salts and sodium EDTAcan also be used as examples of suitable stabilizing agents. Inaddition, parenteral solutions can further comprise at least onepreservative, selected, for example, from benzalkonium chloride, methyl-and propylparaben, and chlorobutanol.

A pharmaceutically acceptable carrier is, for example, selected fromcarriers that are compatible with active ingredients of the composition(and in some embodiments, capable of stabilizing the active ingredients)and not deleterious to the subject to be treated. For example,solubilizing agents, such as cyclodextrins (which can form specific,more soluble complexes with the at least one compound and/or at leastone pharmaceutically acceptable salt disclosed herein), can be utilizedas pharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10. Suitable pharmaceutically acceptable carriers are describedin Remington's Pharmaceutical Sciences, A. Osol, a standard referencetext in the art.

For administration by inhalation, the subject compounds andstereoisomers thereof, and pharmaceutically acceptable salts thereof maybe conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The subject compounds andstereoisomers thereof, and pharmaceutically acceptable salts thereof mayalso be delivered as powders, which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. One exemplary delivery system for inhalation can bemetered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of a subject compound and stereoisomers thereof,and pharmaceutically acceptable salts thereof disclosed herein in atleast one suitable propellant, selected, for example, from fluorocarbonsand hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percentage of a solution or suspension of thesubject compound and stereoisomers thereof, and pharmaceuticallyacceptable salts thereof in an appropriate ophthalmic vehicle, such thatthe subject compound and stereoisomers thereof, and at least onepharmaceutically acceptable salts thereof is maintained in contact withthe ocular surface for a sufficient time period to allow the compound topenetrate the corneal and internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the subjectcompounds and stereoisomers thereof, and pharmaceutically acceptablesalts thereof disclosed herein include, but are not limited to, hard andsoft gelatin capsules, tablets, parenteral injectables, and oralsuspensions.

The dosage administered will be dependent on factors, such as the age,health and weight of the recipient, the extent of disease, type ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. In general, a daily dosage of the active ingredientcan vary, for example, from 0.1 to 2000 milligrams per day. For example,10-500 milligrams once or multiple times per day may be effective toobtain the desired results.

In some embodiments, a large number of unit capsules can be prepared byfilling standard two-piece hard gelatin capsules each with, for example,100 milligrams of the subject compound and stereoisomers thereof, andpharmaceutically acceptable salt thereof disclosed herein in powder, 150milligrams of lactose, 50 milligrams of cellulose, and 6 milligramsmagnesium stearate.

In some embodiments, a mixture of the compound, stereoisomers thereof,and pharmaceutically acceptable salts thereof a digestible oil such assoybean oil, cottonseed oil or olive oil can be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules are washed and dried.

In some embodiments, a large number of tablets can be prepared byconventional procedures so that the dosage unit comprises, for example,100 milligrams of the compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

In some embodiments, a parenteral composition suitable foradministration by injection can be prepared by stirring 1.5% by weightof the compound and/or at least an enantiomer, a diastereomer, orpharmaceutically acceptable salt thereof disclosed herein in 10% byvolume propylene glycol. The solution is made to the expected volumewith water for injection and sterilized.

In some embodiment, an aqueous suspension can be prepared for oraladministration. For example, each 5 milliliters of an aqueous suspensioncomprising 100 milligrams of finely divided compound, stereoisomersthereof, and pharmaceutically acceptable salts thereof, 100 milligramsof sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillincan be used.

The same dosage forms can generally be used when the compound,stereoisomers thereof, and pharmaceutically acceptable salts thereof areadministered stepwise or in conjunction with at least one othertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term coadministrationis understood to include the administration of at least two agentsconcomitantly or sequentially, or alternatively as a fixed dosecombination of the at least two active components.

The compounds, stereoisomers thereof, and pharmaceutically acceptablesalt thereof disclosed herein can be administered as the sole activeingredient or in combination with at least one second active ingredient.

The subject compounds are incorporated into pharmaceutical compositionsor formulations. The compositions will contain pharmaceuticallyacceptable diluents and/or carriers, i. e. diluents or carriers that arephysiologically compatible and substantially free from pathogenicimpurities. Suitable excipients or carriers and methods for preparingadministrable compositions are known or apparent to those skilled in theart and are described in more detail in such publications as Remington'sPharmaceutical Science, Mack Publishing Co, NJ (1991). The compositionsmay also be in the form of controlled release or sustained releasecompositions as known in the art. For many applications the subjectcompounds are administered for morning/daytime dosing, with off periodat night.

The subject compounds may be used per se, or in the form of theirpharmaceutically acceptable salts, such as hydrochlorides,hydrobromides, acetates, sulfates, citrates, carbonates,trifluoroacetates and the like. When compounds contain relatively acidicfunctionalities, salts can be obtained by addition of the desired base,either neat or in a suitable inert solvent. Examples of pharmaceuticallyacceptable base addition salts include sodium, potassium, calcium,ammonium, organic amino, or magnesium salts, or the like. When compoundscontain relatively basic functionalities, salts can be obtained byaddition of the desired acid, either neat or in a suitable inertsolvent. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galacturonic acids and thelike (see, for example, Berge et al, “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19).

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid, and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of this invention.

In addition to salt forms, this invention provides compounds which arein a prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds of the present invention.Additionally, prodrugs can be converted to the compounds of the presentinvention by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to the compounds of thepresent invention when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent. Prodrugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be more bioavailable by oraladministration than the parent drug. The prodrug may also have improvedsolubility in pharmacological compositions over the parent drug. A widevariety of prodrug derivatives are known in the art, such as those thatrely on hydrolytic cleavage or oxidative activation of the prodrug. Anexample, without limitation, of a prodrug would be a compound of thepresent invention which is administered as an ester (the “prodrug”), butthen is metabolically hydrolyzed to the carboxylic acid, the activeentity.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of theinvention.

Some of the subject compounds possess asymmetric carbon atoms (opticalcenters) or double bonds; the racemates, diastereomers, geometricisomers and individual isomers are all intended to be encompassed withinthe scope of the present invention.

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

The compounds are generally administered in a “therapeutically effectiveamount”, i.e. the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. The term “therapeutically effective amount” includes thatamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the condition or disorder being treated. The therapeuticallyeffective amount will vary depending on the compound, the disease andits severity and the age, weight, etc., of the mammal to be treated.

The contacting is generally effected by administering to the subject aneffective amount of one or more compounds having the general formula I(supra), including the various embodiments described above. Generallyadministration is adjusted to achieve a therapeutic dosage of about 0.1to 50, preferably 0.5 to 10, more preferably 1 to 10 mg/kg, thoughoptimal dosages are compound specific, and generally empiricallydetermined for each compound.

The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules, lozenges or the like in the case of solidcompositions. In such compositions, the mimetic is usually a minorcomponent (from about 0.1 to about 50% by weight or preferably fromabout 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form. Unit dosage formulations are preferably about of 5, 10, 25,50, 100, 250, 500, or 1,000 mg per unit. In a particular embodiment,unit dosage forms are packaged in a multipack adapted for sequentialuse, such as blisterpack comprising sheets of at least 6, 9 or 12 unitdosage forms.

The subject compositions may also be coformulated and/or coadministeredwith a different compound which also promotes wakefulness, anti-obesity,and/or recovery from general anesthesia or jet lag. Example ofco-formulatable drugs include diet pills such as Orlistat (Xenical);narcolepsy drugs such as methylphenidate, racemic amphetamine,dextroamphetamine, and methamphetamine, or modafini; stimulants such ascaffeine; etc. In one embodiment, a pharmaceutical composition comprisesone or more compounds of Formula (I) to (VIII) or Formula (A) to (D) ora pharmaceutically acceptable salt or solvate thereof. In oneembodiment, a pharmaceutical composition comprises one or more compoundsof Table I or a pharmaceutically acceptable salt or solvate thereof.

Methods of the Invention

As with the field of modulation of sleep patterns, the molecular basisof the regulation of energy balance and feeding patterns is beginning tobe better understood. The discovery of hypocretins (orexins) and thehypocretin receptors has facilitated the unraveling of the regulatorypathways involved in eating habits. Initially, the finding thatpreprohypocretin RNA molecules and hypocretin-immunoreactive cell bodieswere discretely localized to a subregion of the dorsolateralhypothalamus and a hypothesized colocalization of hypocretins withmelanin concentrating hormone (MCH), a potent orexigeneic peptide,suggested a possible role of this system in the control of feeding (DeLecea et al., 1998). Furthermore, centrally administered hypocretin-1and -2 stimulate appetite in rodents, and preprohypocretin mRNA isupregulated by fasting (Sakurai et al., 1998). However, more recentexperiments suggest a more complex picture. First, the suggested initialcolocalization with MCH was not substantiated by further studies(Broberger et al. (1998) J. Comp. Neurol. 402, 460-474). Second, thereis controversy regarding the magnitude of the effect of hypocretins onfood consumption in rodents (Lubkin et al. (1998) Biochem. Biophys. Res.Commun. 253, 241-245; Edwards et al. (1999) J. Endocrinol. 160, R7-R12;Ida (1999) Brain Res. 821, 526-529; Moriguchi et al. (1999) Neurosci.Lett. 264, 101-104; Sweet (1999) Brain Res. 821, 535-538). For example,while hypocretins stimulate short-term food intake, these peptides donot alter 24 hour total food consumption (Ida et al (1999), supra). Someauthors have also suggested that hypocretins exert a shift in thediurnal pattern of food intake. The effect on energy metabolism seems tobe more pronounced than that on feeding behavior (Lubkin et al. (1998),supra) and differs with the circadian time of administration (Ida et al,(1999), supra). Recent studies suggest complex interactions betweenhypocretins, MCH-containing neurons, neuropeptide Y, agouti gene-relatedprotein systems and leptins in the control of feeding and energy balance(Broberger et al. (1998), supra; Beck et al. (1999) Biochem. Biophys.Res. Commun. 258, 119-122; Horvath et al. (1999). J. Neurosci. 19,1072-1087; Kalra et al. (1999) Endocrine Rev. 20, 68-100; Marsh et al.(1999) Nature Genet. 21, 119-122; Moriguchi et al., supra; Yamamoto etal. (1999) Mol. Brain Res. 65, 14-22).

This invention describes several chemically distinct classes ofnon-peptidic, small-molecule agonists for the type-2 orexin receptors(OX2R). Orexins are hypothalamic neuropeptides that are importantlyimplicated in sleep/wake control and body weight homeostasis. Orexinproducing neurons are exclusively localized in the lateral hypothalamicarea. The peptides act on two G protein-coupled receptors termed OX1Rand OX2R. It has been demonstrated that deficiency in orexin/OX2Rsignaling causes the sleep disorder narcolepsy in humans, mice and dogs.Narcolepsy is a socially debilitating disorder characterized by aninability to properly maintain wakefulness (excessive daytimesleepiness, sleep attacks), and a pathological intrusion of signs of REMsleep into wakefulness (cataplexy, hipnagorgic hallucination, sleepparalysis, etc).

A transgenic mouse strain that has been engineered to mimic theneurochemical situation in human narcoleptics, i.e., with a postnatalloss of orexin neurons, exhibits all symptoms of narcolepsy/cataplexy.It has been further demonstrated that these mice can then be effectivelytreated for narcolepsy by providing exogenous orexin either genetically(via a transgene) or pharmacologically (via intracerebroventricularinjections). Hence, orexin replacement therapy is expected to providesimilarly effectively treat human narcolepsy patients.

Orexins themselves are peptides (thus orally inactive) and blood-brainbarrier impermeable; they cannot be used as an orally active therapeuticagent. However, if we can develop an orally active, blood-brain barrierpermeable, small-molecule OX2R agonist, such compound will be useful asa drug for the treatment of narcolepsy.

The practical uses for OX2R agonists go beyond the treatment ofnarcolepsy. Since orexin has been established as an endogenousneurotransmitter to maintain proper wakefulness, orexin receptoragonists effect a highly “natural” form of wakefulness. Therefore, suchagonists may be used to treat medical conditions accompanyingnarcolepsy, daytime sleepiness, such as nighttime insomnia, anddepression with hypersomnia.

It has also been shown that orexin/OX2R signaling acts as a net-negativeregulator of body weight homeostasis. Thus, deficiencies in OX2Rsignaling can cause (besides narcolepsy) obesity in mice and humans,whereas transgenic OX2R over-activation renders mice resistant to highfat diet-induced obesity. Furthermore, intracerebroventricular infusionof a previously known peptidic OX2R-selective agonist similarly preventshigh fat diet-induced obesity in mice. Therefore, orally active OX2Ragonists also provide treatments of obesity and associated metabolicsyndrome.

Orexin deficiency causes delayed recovery from gas anesthesia in mice,which effect can be antagonized by orexin and orexin agonists. See, Kelzet al. An essential role for orexins in emergence from generalanesthesia. Proc. Natl. Acad. Sci. USA 105:1309-1314 (2008). Hence, thesubject orexin agonists may also be used to facilitate or expediterecovery from general anesthesia.

The active OX2R agonists provided in this invention also provide leadcompounds for the development of alternative and more potent forms withdesirable pharmacokinetics, bioavailability, nontoxicity, and otherproperties. Such derivative compounds may be used, inter alia and afterproper clinical trials, as therapeutic agents for treating (1)narcolepsy; (2) other neurologic conditions accompanying daytimesleepiness, such as night time insomnia and depression with hypersomnia,sleep apnea, jet lag, etc.; (3) obesity and metabolic syndrome; and (4)undesirable extension and lingering effects of general anesthesia.

The present disclosure thus relates to the use of one or more agents orone or more compounds of Formula (I) to (VIII) or Formula (A) to (D) ora pharmaceutically acceptable salt or solvate thereof as an agonist of atype-2 orexin receptor (OX2R). In another embodiment, the presentdisclosure relates to the use of one or more agents or one or morecompounds of Table I or a pharmaceutically acceptable salt or solvatethereof as an agonist of a type-2 orexin receptor (OX2R). As agonists ofOX2R, the compounds of the present invention may be administered to asubject with various diseases, disorders or medical conditions.

In a specific embodiment, the methods of the present invention mayinclude treating a subject suffering from or diagnosed with a disease,disorder, or medical condition mediated by orexin receptor activity,wherein the disease, disorder, or medical condition is a disorder of thesleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbedsleep, a sleep disorder secondary to neurological disorders, mania,depression, manic depression, schizophrenia, a pain syndromes,fibromyalgia, neuropathic pain, catatonia, Parkinson's disease,Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity ora condition related to overweight or obesity, insulin resistance, typeII diabetes, hyperlipidemia, gallstones, angina, hypertension,breathlessness, tachycardia, infertility, sleep apnea, back and jointpain, varicose veins, osteoarthritis, hypertension, tachycardia,arrhythmias, angina pectoris, acute heart failure, ulcers, irritablebowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stressdisorder, panic disorders, attention deficit disorders, cognitivedeficiencies, or substance abuse, comprising administering to thesubject an effective amount of any compound of Formula (I) to (VIII),Formula (A) to (D), Table I, or a pharmaceutically acceptable saltthereof.

In a specific embodiment, the methods may include the treatment of oneor more sleep disorders, comprising administering to the subject aneffective amount of any compound of Formula (I) to (VIII), Formula (A)to (D), Table I, or a pharmaceutically acceptable salt thereof.

In another embodiment, the methods may include promoting or enhancingwakefulness, anti-obesity, or recovery from general anesthesia or jetlag in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of any compound of Formula (I)to (VIII), Formula (A) to (D), or Table I, or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the methods may include increasing resistance todiet-induced accumulation of body fat, comprising administering to thesubject an effective amount of any compound of Formula (I) to (VIII),Formula (A) to (D), Table I, or a pharmaceutically acceptable saltthereof.

In another embodiment, the methods may include shortening recoveryperiod from general anesthesia or jet lag, comprising administering tothe subject an effective amount of any compound of Formula (I) to(VIII), Formula (A) to (D), Table I, or a pharmaceutically acceptablesalt thereof.

In another embodiment, the methods may include treating narcolepsy in asubject in need thereof, comprising administering to the subject aneffective amount of oany compound of Formula (I) to (VIII), Formula (A)to (D), Table I, or a pharmaceutically acceptable salt thereof.

In another embodiment, the methods may include agonizing a type-2 orexinreceptor (OX2R), comprising contacting the OX2R with a compound of anycompound of Formula (I) to (VIII), Formula (A) to (D), Table I, or apharmaceutically acceptable salt thereof.

In a specific embodiment, the contacting is in a cell.

In another specific embodiment, the compound is administered to thesubject regularly and/or chronically. In another embodiment, thecompound is administered to the subject orally.

Examples

General Synthesis

The compound of the present disclosure can be prepared followingprotocols described in US 2014/0051700 and/or U.S. Pat. No. 8,871,794,the disclosures of which are hereby incorporated by reference in theirentireties and common organic chemistry synthesis protocols known to oneskilled in the art. Also see

-   [1] Allen, John Gordon et al. 6 substituted 2, 3,4,5    tetrahydro-1H-benzo[d]azepines as 5-HT2C receptor agonist. U.S. Ser.    No. 10/598,302, Feb. 18, 2005.-   [2] Ali, A. et al. Cholesteryl ester transfer protein inhibitors.    U.S. Pat. No. 8,865,707, Oct. 21, 2014-   [3] Clive, D. L. J. and Huang, X. J. Org. Chem. 2004, 69, 1872-1879-   [4] Schnapperelle, I. et al. Chem. Eur. J. 2012, 18, 1073-1076-   [5] Arp, F. O. and Fu, G. C. J. Am. Chem. Soc. 2005, 127,    10482-10483-   [6] Qin, C. and Davies, H. M. J. Am. Chem. Soc. 2014, 136, 9792-9796-   [7] Tino, J. A. Heterocyclic aromatic compounds useful as growth    hormone secretagogues U.S. Pat. No. 6,525,203, 25 Feb. 2003-   [8] Welch, J. T. and Seper, K. W. J. Org. Chem. 53(13), 1988,    2991-2999-   [9] Dixon, D. L. et al. Org. Lett. 2013, 15, 2946-2949-   [10] Ueda, H. et al. Org. Lett. 2014, 16, 4194-4197    each of which are hereby incorporated by reference in their    entireties.

In general, the subject compounds may be prepared by a stepwisealkylation of 2-aminobenzimidazole (Scheme 1) or a ring-substituted2-aminobenzimidazole where R⁶ is other than hydrogen (Scheme 2).°

In the first alkylation, the sodium salt of 2-aminobenzimidazole reactssmoothly with alkyl and benzyl chlorides (Joseph, J Med Chem 28: 601(1963); Ogura et al, J Med Chem 15: 923-926 (1972)). The secondalkylation proceeds under conditions of high concentration in refluxingtoluene, reacting exclusively at the 3-position of the imidazole moiety(Rehse, et al., Arch Pharm (Weinheirn) 328: 77-80, 1995). Theprecipitation of the product as the hydrobromide salt prohibitsadditional alkylation and simplifies the purification.

Alternatively, as described below with respect to the preparation of acombinatorial library, the compounds can be prepared by a process inwhich a resin-bound 4-fluoro-3-nitroarene is reacted with an aminehaving the formula W²L²-NH₂, reduced with tin (II) chloride (Bellamy, etal., Tetrahedron Lett 25: 839-842, 1984), cyclized with cyanogen bromide(U.S. Pat. No. 4,002,623), and reacted with a mono-substituted epoxide.

If R⁶ is a group having the formula —CONR′R″ that group is firstintroduced by amide coupling with the fluoronitrobenzoic acid.

General Procedure (A) to Convert Alcohols to Bromides Through AppelReaction

To a flame-dried flask were added an arylmethyl alcohol (1.0 eq.),anhydrous DCM (1.94 mL/mmol) and CBr₄ (1.1 eq.), followed by addition ofPPh₃ (1.1 eq.) in portions under argon. The resulting reaction mixturewas stirred at room temperature for 40 min and was then filtered througha short pad of celite. Upon the evaporation of the solvent, the residuewas purified through flash chromatography on silica gel (9:1 or 2:1hexane/EtOAc) to provide the desired product.

General Procedure (B) for the Synthesis of ethyl2-amino-3-arylpropanoates

To a flame-dried flask containing t-BuOK (1.10 equiv.) and anhydrous DMF(2.5 mL/mmol) was added ethyl 2-((diphenylmethylene)amino)acetate (1.05eq.) at 0° C. under argon. After 10 min, arylmethyl bromide (1.0 eq.)was added. The resulting reaction mixture was stirred at 0° C. for 10min and was allowed to warm up to 4° C. and stirred at 4° C. overnight.The reaction mixture was then slowly poured into water, extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to evaporate the DCM solvent. Theresidue was then treated with a mixture of EtOH/concentrated HCl (25:1v/v). The resulting solution was stirred at room temperature for 2 h.Upon the evaporation of EtOH and most of the DMF, the residue wasbasified by 2 N K₂CO₃ solution to pH>10 and extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified throughflash chromatography on silica gel (1:19 CH₃OH/CH₂Cl₂) to afford thedesired ethyl 2-amino-3-arylpropanoate product as a colorless gel.

General Procedure (C) for the Synthesis of ethyl2-((2-nitrophenyl)amino)-3-arylpropanoates Through SNAr Reaction Between1-fluoro-2-nitrobenzene and ethyl 2-amino-3-arylpropanoates

To a mixture of ethyl 2-amino-3-arylpropanoate (1.0 eq.) and DMF (3mL/mmol) were added 1-fluoro-2-nitrobenzene (1.05 eq.) and NaHCO₃ (1.20eq.). The resulting reaction suspension was then stirred rigorously at100° C. overnight and cooled down to room temperature. The suspensionwas filtered through a pad of celite and the filter cake was washed by asmall amount of DCM. Upon the evaporation of the solvents under reducedpressure, the residue was purified through flash chromatography onsilica gel (EtOAc/hexane) to afford the ethyl2-((2-nitrophenyl)amino)-3-arylpropanoate as a yellow gel.

General Procedure (D) for the Synthesis of2-((2-aminophenyl)amino)-3-arylpropan-1-ols

To a flame-dried flask were added lithium aluminum hydride (2.0 eq.) andanhydrous THF (7 mL/mmol) at 0° C., followed by addition of the ethyl2-((2-nitrophenyl)amino)-3-arylpropanoate (1.0 eq.) under argon. Theresulting reaction mixture was stirred at 0° C. for 1 h and 1 N KOHsolution was added dropwise at 0° C. to quench the reaction. Upon theaddition of KOH solution, the mixture was stirred for 15 more min at 0°C. and was condensed under reduced pressure to evaporate most of theTHF. The residue was then mixed with water and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford a mixture of the2-((2-aminophenyl)amino)-3-arylpropan-1-ol (major one) and the ethyl2-((2-nitrophenyl)amino)-3-arylpropanoate (minor one).

To a flask were added the mixture above, methanol (8 mL/mmol) and Pd/C(10% on active carbon). The reaction flask was sealed by a septum andafter the removal of air using vacuum, a hydrogen balloon was fitted onthe top of the septum. The reaction suspension was then stirred at roomtemperature for 18 h and was filtered through a pad of celite. Thefiltrate was concentrated under reduced pressure and the residue waspurified through flash chromatography on silica gel (1:19 CH₃OH/CH₂Cl₂)to provide the 2-((2-aminophenyl)amino)-3-arylpropan-1-ol as a browngel.

General Procedure (E) for the Synthesis of2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-arylpropan-1-olsthrough cyclization and alkylation

To a solution of 2-((2-aminophenyl)amino)-3-arylpropan-1-ol (1.0 eq.) inMeOH (4.5 mL/mmol) was added cyanogen bromide (3 M in DCM, 1.2 eq.). Theresulting solution was stirred at room temperature with a reaction timeranging from 2 h to 12 h (until TLC indicated the complete consumptionof the 2-((2-aminophenyl)amino)-3-arylpropan-1-ol) and after theevaporation of solvents, the residue was treated with saturated NaHCO₃solution (after which the aqueous layer's pH is about 8˜9) and thenextracted with DCM. The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-arylpropan-1-ol as adark brown gel.

To a flask equipped with a reflux condenser and stirring bar were addedthe 2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-arylpropan-1-ol(1.0 eq.), 2-butanone (12 mL/mmol) and arylmethyl bromide (1.2 eq.). Theresulting mixture was stirred at 75° C. overnight and then cooled toroom temperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (40 mL/mmol) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was treated with saturated NaHCO₃solution, extracted with DCM. The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-arylpropan-1-olas a brown gel.

General Procedure (F) of Synthesis of Pyridone Analogs fromDemethylation of the Methoxypyridine Precursors

To a flame-dried flask equipped with a reflux condenser and stirring barwere added methoxypyridine analog (1.0 eq.), anhydrous CH₃CN (42mL/mmol), NaI (4.0 eq.) and Me₃SiCl (10.5 eq.). The resulting mixturewas stirred at 75° C. for 3.5 h and then cooled to room temperature. 20%NH₄H solution (50 mL/mmol) was then added to the reaction solutionslowly and after the evaporation of CH₃CN, the remaining slurry solutionwas diluted with water (80 mL/mmol) and extracted with a mixture ofDCM/Methanol (10:1, 3×160 mL/mmol). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the entitled product as a brown foam.

General Procedure (G) for the Synthesis of Boc Protected Amide AnalogsThrough the Reaction Betweentert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamateand acyl chlorides

To a flask containingtert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(1.0 eq.) were added sequentially DCM (14 mL/mmol), Et₃N (1.5 eq.) andacyl chloride (1.2 eq.). The resulting solution was stirred at rt for 17h and was diluted with DCM (70 mL/mmol), washed by saturated NaHCO₃solution (70 mL/mmol). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purifiedthrough flash chromatography on silica gel (1:19 methanol/DCM) to affordthe Boc protected amide analogs.

General Procedure (H) for the Boc Deprotection of Boc Protected AmideAnalogs Using TFA in Anhydrous DCM

To a solution of Boc protected amide analog (1.0 eq.) in anhydrous DCM(40 mL/mmol) was added TFA (80 eq.). The resulting solution was stirredat rt for 3 h-6 h and was poured into 2N K₂CO₃ solution (600 mL/mmol),extracted with DCM (3×600 mL/mmol). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the amide analogs.

General Procedure (I) of the Synthesis of Boc Protected Amide AnalogsThrough EDC Amide Coupling Reaction Betweentert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamateand carboxylic acids

To a flask were addedtert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(1.0 eq.), carboxylic acid (1.1 eq.), DMAP (0.3 eq.) (or HOBt (1.5eq.)), EDC hydrochloride (1.2 eq.) and DCM (20 mL/mmol) [or DMF (2.5mL/mmol) if HOBt was used]. The resulting solution was stirred for 24 hat rt and was diluted with DCM (140 mL/mmol), washed by brine (140mL/mmol) and sat. NaHCO₃ solution (140 mL/mmol). The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified through flash chromatography on silica gel (1:19methanol/DCM) to afford the Boc protected amide analogs.

General Procedure (J) for Synthesis Boc Protected Sulfonamide AnalogsThrough the Reaction Betweentert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamateand sulfonyl chlorides

tert-Butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(1.0 eq.) was dissolved in DCM (5 mL/mmol), and DIPEA (3.0 eq.) wasadded. The solution was cooled to 0° C., and sulfonyl chloride (1.2 eq)was added. The solution was allowed to warm to ambient temperatureovernight. Upon completion, the reaction was diluted with satd. aq.NaHCO₃, and the organic layer was loaded directly onto a silica columnand purified (SiO₂, 0-30% or 50% EtOAc/DCM) to afford the Boc protectedsulfonamides.

General Procedure (K) for the Boc Deprotection of Boc ProtectedSulfonamide or Amide Analogs Using HCl in 1,4-dioxane

Boc protected sulfonamide analogs (1.0 eq.) was dissolved in 4 MHC/1,4-dioxane (5.1 mL/mmol). The mixture was stirred at ambienttemperature for 3.5 h, during which a white precipitate developed. Uponcompletion, the reaction was concentrated under a stream of air, driedunder vacuum, and triturated 2× with Et₂O to remove any non-polarimpurities. The resulting white solid was suspended in DCM, and satd.aq. NaHCO₃ was added to free-base the product. The bi-phasic mixture wasstirred for 45 min, after which the layers were separated, and theaqueous layer was extracted twice more with DCM. The combined organiclayers were passed through a plug of MgSO₄ and concentrated to affordthe Boc deprotected sulfonamides.

General Procedure (L) for Nitro Compound Synthesis

At room temperature, fluoro-nitro-pyridine (fluoro-nitro-benzene) (1eq.), amino alcohol (ether, ester) (1 eq.), such as(S)-2-amino-3-(p-tolyl)propan-1-ol, and potassium carbonate (excess) aremixed in dimethylformamide. The reaction was stirred at room temperaturefor overnight. After filtration and removing solvent, the residue waspurified by flash chromatography using 20-30% hexanes in ethyl acetateas eluent. Giving diamine compounds, such as(S)-2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol, as yellowsolid or oil.

Alternatively, to a solution of amine (1 eq.). such as(S)-2-amino-N-methyl-3-(p-tolyl)propanamide, in DMF was added1-fluoro-2-nitrobezene (1 eq.) and potassium carbonate (2 eq.). Themixture was stirred at 80° C. for overnight. After filtration thefiltrate was concentrated at reduced pressure and the residue waspurified using 50% ethyl acetate in hexanes as eluent, giving product,such as (S)—N-methyl-2-((2-nitrophenyl)amino)-3-(p-tolyl)propenamide, asyellow solid.

Alternatively, to a solution of amine (1 eq.) in DCM was addedtriethylamine (3 eq.) followed by addition of boc protected amino acid(1.3 eq.) and BOP reagent (1.3 eq.). The mixture was stirred at roomtemperature for overnight. Solvent was removed, and the residue waspurified by flash chromatography using 40% ethyl acetate in hexanes aseluent. Giving product as yellow solid.

General Procedure (M) for Nitro Compound to Diamine Compound Synthesis

At room temperature, nitro compounds, such as(S)-2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol, and palladiumon charcoal (or Raney nickel) was mixed in methanol (or acetonitrile).The mixture was stirred at room temperature for 3-48 hours as the yellowcolor disappeared. After filtration to remove palladium on charcoal (orRaney nickel), solvent was removed, and the crude diamine product, suchas (S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol was used innext step without purification.

General Procedure (N) for Diamine Compound Synthesis with 4-MethylBenzyl Bromide

At room temperature, substituted anilines (1 eq.), such as(S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol, 4-methylbenzyl bromide (1 eq.) and potassium carbonate (1 eq.) were mixed indimethylformamide. The mixture was stirred at room temperature forovernight, followed by filtration to filter off the potassium carbonate.After removing solvent, the residue was purified by flash chromatographyusing 20-50% ethyl acetate in hexanes as eluent to provide diaminecompound, such as(S)-2-((3-((4-methylbenzyl)amino)pyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol.

General Procedure (O) for Diamine Compound Synthesis with SecondaryBromide

At room temperature, substituted anilines (1 eq.), such as(S)-2-((2-aminophenyl)amino)-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-one,secondary bromide (1 eq.), such as 1-(1-bromoethyl)-4-methylbenzene, andpotassium carbonate (1 eq.) were mixed in dimethylformamide. The mixturewas stirred at 80° C. for overnight, followed by filtration to filteroff the potassium carbonate. After removing solvent, the residue waspurified by flash chromatography using 20-50% ethyl acetate in hexanesas eluent to provide the diamine compound, such as(2S)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.

General Procedure (P) for Diamine Compound to Final Products

At room temperature, to the solution of diamine substrate, such as(S)—N1-(1-methoxy-3-phenylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine, (1 eq.) in methanol (5 mL) was addedcyanogen bromide (4 eq., 3M solution in dichloromethane). The mixturewas stirred at room temperature for 4-48 hours. After completion of thereaction, the solvent was removed under reduced pressure. The remainingsolid was mixed with saturated NaHCO₃ solution (25 m), extracted withCH₂Cl₂ (3×25 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on Biotage Isolera system using5% methanol in dichloromethane as eluent to provide the target compound,such as(S)-1-(1-methoxy-3-phenylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-iminn.

Synthesis with General Procedure (A).

(6-methoxypyridin-2-yl)methanol. This compounds was prepared followingthe method described by Allen, J. G. et al. To a flask were added2-Methoxy-6-pyridinecarboxaldehyde (1.4445 g, 10.54 mmol), THF (15 mL)and water (1.5 mL). The resulting solution was stirred at roomtemperature and NaBH₄ (0.4639 g, 12.21 mmol) was added in 7 min. Theresulting reaction mixture was stirred at room temperature for 1.5 h andwas poured into brine (60 mL), extracted with DCM (2×60 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified through ashort pad of silica gel, eluted with a mixture of 3:1 hexane/EtOAc toprovide the desired product as a yellow liquid (1.4455 g, >95%). ¹H NMR(400 MHz, CDCl₃) δ 7.55 (dd, J=8.2, 7.3 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H),6.62 (d, J=8.2 Hz, 0H), 4.66 (d, J=4.6 Hz, 2H), 3.94 (s, 3H), 3.56 (t,J=4.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 163.6, 156.9, 139.2, 112.7,109.0, 63.9, 53.3.

2-(bromomethyl)-6-methoxypyridine. Reaction of(6-methoxypyridin-2-yl)methanol (Procedure A) yielded the title productas a colorless liquid (73%). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (t, J=8.4Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 4.45 (s, 2H),3.93 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 163.8, 154.2, 139.2, 115.9,110.4, 53.5, 34.1. LC-MS (ESI) calcd for: C₇H₉BrNO (MH⁺): 202.0, found202.0.

2-(bromomethyl)pyridine. Reaction of pyridin-2-ylmethanol (Procedure A)yielded the title product as a maroon gel (>95%). ¹H NMR (400 MHz,CDCl₃) δ 8.56 (d, J=4.9 Hz, 1H), 7.67 (td, J=7.7, 1.8 Hz, 1H), 7.42 (d,J=7.8 Hz, 1H), 7.19 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 4.53 (s, 2H). ¹³C NMR(100 MHz, CDCl₃) δ 156.8, 149.6, 137.1, 123.4, 123.0, 33.8.

4-(bromomethyl)-2-methoxypyridine. Reaction of(2-methoxypyridin-4-yl)methanol (Procedure A) yielded the title producta colorless liquid (70%). ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=5.3 Hz,1H), 6.88 (d, J=5.4 Hz, 1H), 6.73 (s, 1H), 4.32 (s, 2H), 3.93 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 164.5, 148.7, 147.4, 116.9, 110.6, 53.6,30.5.

Synthesis with General Procedure (B).

Ethyl 2-amino-3-(6-methoxypyridin-2-yl)propanoate. Reaction of2-(bromomethyl)-6-methoxypyridine (Procedure B) yielded the titleproduct (86%). ¹H NMR (400 MHz, CDCl₃) δ 7.45 (dd, J=8.3, 7.2 Hz, 1H),6.70 (d, J=7.2 Hz, 1H), 6.55 (d, J=8.3 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H),3.98-3.88 (m, 1H), 3.86 (s, 3H), 3.15 (dd, J=14.6, 4.7 Hz, 1H), 3.04(dd, J=14.4, 7.2 Hz, 1H), 1.82 (s, 2H), 1.21 (t, J=7.2 Hz, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 175.3, 163.6, 155.4, 138.8, 116.4, 108.5, 60.8, 53.9,53.3, 41.6, 14.2. LC-MS (ESI) calcd for: C₁₁H₁₇N₂O₃ (MH⁺): 225.1, found225.1.

Ethyl 2-amino-3-(p-tolyl)propanoate. Reaction of 4-methylbenzylbromide(Procedure B) yielded the title product (95%). ¹H NMR (400 MHz, CDCl₃) δ7.13-7.02 (m, 4H), 4.15 (q, J=7.2 Hz, 2H), 3.66 (dd, J=7.9, 5.2 Hz, 1H),3.03 (dd, J=13.5, 5.2 Hz, 1H), 2.80 (dd, J=13.5, 7.9 Hz, 1H), 2.30 (s,3H), 1.47 (s, 2H), 1.23 (t, J=7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ175.1, 136.3, 134.1, 129.2, 129.2, 60.8, 55.9, 40.7, 21.0, 14.2; LC-MS(ESI) calcd for: C12H18NO2 (MH⁺): 208.1, found 208.1.

Ethyl 2-amino-3-(pyridin-2-yl)propanoate. Reaction of2-(bromomethyl)pyridine (Procedure B) yielded the title product (25%).¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=4.2 Hz, 1H), 7.58 (t, J=7.6 Hz,1H), 7.21-7.01 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.94 (dd, J=8.2, 4.7 Hz,1H), 3.24 (dd, J=14.1, 4.7 Hz, 1H), 3.01 (dd, J=13.7, 8.2 Hz, 1H), 1.82(s, 2H), 1.20 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 175.1,158.0, 149.3, 136.3, 123.9, 121.6, 60.9, 54.4, 42.6, 14.1. LC-MS (ESI)calcd for: C₁₀H₁₄N₂O₂ (MH⁺): 195.1, found 195.1.

Ethyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate. Reaction of4-(bromomethyl)-2-methoxypyridine (Procedure B) yielded the titleproduct (61%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=4.8 Hz, 1H), 6.69(d, J=5.3 Hz, 1H), 6.55 (s, 1H), 4.13 (qd, J=7.2, 1.5 Hz, 2H), 3.87 (d,J=1.4 Hz, 3H), 3.75-3.58 (m, 1H), 2.97 (dd, J=13.6, 5.4 Hz, 1H), 2.75(dd, J=13.6, 8.0 Hz, 1H), 1.51 (s, 2H), 1.21 (td, J=7.2, 1.5 Hz, 3H).¹³C NMR (100 MHz, CDCl₃) δ 174.5, 164.4, 149.2, 146.8, 117.8, 111.3,61.1, 55.0, 53.3, 40.2, 14.1.

Ethyl phenylalaninate. Reaction of benzylbromide (Procedure B) yieldedthe title product (>98%). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.26 (m, 2H),7.24-7.15 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 3.68 (dd, J=7.8, 5.4 Hz, 1H),3.05 (dd, J=13.5, 5.4 Hz, 1H), 2.84 (dd, J=13.5, 7.9 Hz, 1H), 1.46 (s,2H), 1.21 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 175.0, 137.3,129.3, 128.5, 126.7, 60.9, 55.9, 41.2, 14.2.

Synthesis with General Procedure (C).

Ethyl 3-(6-methoxypyridin-2-yl)-2-((2-nitrophenyl)amino)propanoate.Reaction of ethyl 2-amino-3-(6-methoxypyridin-2-yl)propanoate (ProcedureC) yielded the title product (32%). ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d,J=7.6 Hz, 1H), 8.15 (dd, J=8.6, 1.6 Hz, 1H), 7.47 (dd, J=8.3, 7.2 Hz,1H), 7.43-7.37 (m, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H),6.67 (ddd, J=8.4, 7.0, 1.2 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 4.72 (dd,J=13.5, 6.0 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.94 (s, 3H), 3.33 (d,J=6.0 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.6,163.9, 153.7, 144.1, 139.0, 136.1, 132.6, 126.9, 116.3, 116.0, 113.8,109.3, 61.5, 55.5, 53.5, 39.8, 14.1. LC-MS (ESI) calcd for: C17H20N3O5(MH⁺): 346.1, found 346.2.

Ethyl 3-(6-methoxypyridin-2-yl)-2-((2-nitrophenyl)amino)propanoate.Reaction of ethyl 2-amino-3-(p-tolyl)propanoate (Procedure C) yieldedthe title product (44%). ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=7.3 Hz,1H), 8.16 (dd, J=8.8, 1.6 Hz, 1H), 7.44-7.34 (m, 1H), 7.12 (s, 4H),6.72-6.62 (m, 2H), 4.53-4.35 (m, 1H), 4.19 (qd, J=7.1, 1.0 Hz, 2H),3.35-3.05 (m, 2H), 2.31 (s, 3H), 1.22 (t, J=7.1 Hz, 3H). ¹³C NMR (100MHz, CDCl₃) δ 171.5, 143.9, 137.0, 136.1, 132.4, 129.5, 129.1, 127.0,116.2, 113.8, 110.0, 61.6, 57.5, 38.2, 21.1, 14.1. LC-MS (ESI) calcdfor: C₁₈H₂₁N₂O₄ (MH⁺): 329.2, found 329.2.

Ethyl 2-((2-nitrophenyl)amino)-3-(pyridin-2-yl)propanoate. Reaction ofethyl 2-amino-3-(pyridin-2-yl)propanoate (Procedure C) yielded the titleproduct (32%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (d, J=7.6 Hz, 1H), 8.57(d, J=4.9 Hz, 1H), 8.12 (dd, J=8.5, 1.7 Hz, 1H), 7.58 (td, J=7.7, 1.9Hz, 1H), 7.36 (ddd, J=8.6, 6.9, 1.7 Hz, 1H), 7.20-7.10 (m, 2H), 6.76 (d,J=8.7 Hz, 1H), 6.64 (ddd, J=8.3, 6.9, 1.2 Hz, 1H), 4.75 (td, J=7.3, 5.7Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.38 (qd, J=14.0, 6.3 Hz, 2H), 1.17 (t,J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 156.2, 149.6, 144.0,136.6, 136.1, 132.7, 126.9, 123.9, 122.2, 116.1, 113.9, 61.6, 55.8,40.4, 14.1. LC-MS (ESI) calcd for: C16H18N3O4 (MH⁺): 316.1, found 316.1.

Ethyl 3-(2-methoxypyridin-4-yl)-2-((2-nitrophenyl)amino)propanoate.Reaction of ethyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate (ProcedureC) yielded the title product (10%). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d,J=7.6 Hz, 1H), 8.22-8.14 (m, 1H), 8.08 (d, J=5.3 Hz, 1H), 7.50-7.34 (m,1H), 6.81-6.65 (m, 3H), 6.60 (s, 1H), 4.47 (td, J=7.4, 5.6 Hz, 1H), 4.20(q, J=7.1 Hz, 2H), 3.90 (s, 3H), 3.35-3.01 (m, 2H), 1.22 (t, J=7.1 Hz,3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 164.6, 147.3, 147.2, 143.5,136.2, 132.9, 127.1, 117.6, 116.6, 113.6, 111.3, 61.9, 56.5, 53.4, 37.7,14.1. MS (ESI) calcd for: C17H20N3O5 (MH⁺): 346.1, found 346.1.

Ethyl (2-nitrophenyl)phenylalaninate. Reaction of ethyl phenylalaninate(Procedure C) yielded the title product (39%). ¹H NMR (400 MHz, CDCl₃) δ8.36 (d, J=7.3 Hz, 1H), 8.17 (dd, J=8.9, 1.6 Hz, 1H), 7.39 (t, J=8.6 Hz,1H), 7.35-7.26 (m, 3H), 7.25-7.20 (m, 2H), 6.73-6.62 (m, 2H), 4.45 (td,J=7.4, 5.7 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.36-3.11 (m, 2H), 1.21 (t,J=7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 143.9, 136.1, 135.6,129.2, 128.8, 127.4, 127.0, 116.3, 113.7, 61.7, 57.5, 38.7, 14.1. MS(APCI) calcd for: C17H19N2O4 (MH⁺): 315.1, found 315.1.

Synthesis with General Procedure (D).

2-((2-aminophenyl)amino)-3-(6-methoxypyridin-2-yl)propan-1-ol. Reactionof ethyl 3-(6-methoxypyridin-2-yl)-2-((2-nitrophenyl)amino)propanoate(Procedure D) yielded the title product (68% two steps). ¹H NMR (400MHz, Methanol-d4) δ 7.55 (t, J=7.8 Hz, 1H), 7.18-6.98 (m, 3H), 6.93-6.76(m, 2H), 6.61 (d, J=8.3 Hz, 1H), 4.17-4.00 (s, 1H), 3.87 (s, 3H),3.74-3.58 (br, 2H), 3.01 (d, J=6.9 Hz, 2H). ¹³C NMR (100 MHz,Methanol-d4) δ 163.9, 155.9, 139.4, 135.7, 126.0, 124.6, 121.7, 120.5,116.5, 107.5, 61.7, 56.5, 52.7, 37.7. MS (ESI) calcd for: C15H20N3O2(MH⁺): 274.2, found 274.2.

2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol. Reaction of ethyl2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoate (Procedure D) yielded thetitle product (35% two steps). ¹H NMR (400 MHz, Methanol-d4) δ 7.10 (dd,J=23.4, 7.6 Hz, 4H), 6.81-6.64 (m, 3H), 6.63-6.51 (m, 1H), 3.72-3.42 (m,3H), 2.83 (d, J=6.1 Hz, 2H), 2.27 (s, 3H). ¹³C NMR (100 MHz,Methanol-d4) δ 135.9, 135.8, 135.3, 135.1, 128.9, 128.6, 119.7, 118.5,116.5, 113.3, 62.1, 56.4, 36.4, 19.7. MS (ESI) calcd for: C₁₆H₂₁N₂O(MH⁺): 257.2, found 257.2.

2-((2-aminophenyl)amino)-3-(pyridin-2-yl)propan-1-ol. Reaction of ethyl2-((2-nitrophenyl)amino)-3-(pyridin-2-yl)propanoate (Procedure D)yielded the title product (53% two steps). ¹H NMR (400 MHz, Methanol-d4)δ 8.43 (d, J=5.1 Hz, 1H), 7.68 (td, J=7.7, 1.7 Hz, 1H), 7.34 (d, J=7.8Hz, 1H), 7.20 (ddd, J=7.7, 5.0, 1.2 Hz, 1H), 6.72-6.60 (m, 3H), 6.54(ddd, J=7.6, 7.0, 1.9 Hz, 1H), 3.89-3.77 (m, 1H), 3.58 (d, J=4.7 Hz,2H), 3.06 (qd, J=13.7, 6.8 Hz, 2H). ¹³C NMR (100 MHz, Methanol-d4) δ159.3, 148.2, 137.1, 135.7, 134.9, 124.4, 121.6, 119.6, 118.4, 116.4,113.0, 62.6, 55.4, 39.3.

2-((2-aminophenyl)amino)-3-(2-methoxypyridin-4-yl)propan-1-ol. Reactionof ethyl 3-(2-methoxypyridin-4-yl)-2-((2-nitrophenyl)amino)propanoate(Procedure D) yielded the title product (60% two steps). ¹H NMR (400MHz, Methanol-d4) δ 8.00 (d, J=5.3 Hz, 1H), 6.89 (d, J=5.5 Hz, 1H),6.81-6.62 (m, 4H), 6.62-6.52 (m, 1H), 3.85 (s, 3H), 3.79-3.62 (m, 1H),3.55 (d, J=4.8 Hz, 2H), 3.01-2.67 (m, 2H). ¹³C NMR (100 MHz,Methanol-d4) δ 164.51, 152.25, 145.87, 135.56, 134.98, 119.63, 118.51,118.14, 116.47, 113.09, 110.63, 62.24, 55.37, 52.66, 36.33.

2-((2-aminophenyl)amino)-3-phenylpropan-1-ol. Reaction of ethyl(2-nitrophenyl)phenylalaninate (Procedure D) yielded the title product(78% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.28 (m, 2H), 7.26-7.14(m, 3H), 6.95-6.62 (m, 4H), 3.79-3.65 (m, 2H), 3.51 (dd, J=10.4, 4.6 Hz,1H), 3.42-3.05 (br, 3H), 2.97 (dd, J=13.6, 5.6 Hz, 1H), 2.85 (dd,J=13.6, 7.5 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 138.3, 136.1, 135.2,129.3, 128.6, 126.5, 120.7, 119.6, 117.2, 114.2, 63.0, 56.1, 37.6. MS(APCI) calcd for: C15H19N2O (MH⁺): 243.2, found 243.4.

Synthesis with General Procedure (E).

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(2-methoxypyridin-3-yl)propan-1-ol (ARN-17)

To a flask equipped with a reflux condenser and stirring bar were added2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-2-yl)propan-1-ol(0.1 g, 0.50 mmol), 2-butanone (10 mL) and1-(bromomethyl)-4-methylbenzene (0.111 g, 0.60 mmol). The resultingmixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 m), extracted with CH₂Cl₂ (3×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the entitled free amine product as a brown gel (0.16 g, 79%);¹H NMR (400 MHz, CDCl₃) δ 7.94 (dd, J=4.9, 1.9 Hz, 1H), 7.41 (dd, J=7.2,2.0 Hz, 1H), 7.21-7.02 (m, 4H), 6.98-6.60 (m, 5H), 4.96-4.77 (m, 2H),4.56 (td, J=7.7, 4.2 Hz, 1H), 4.14-3.92 (m, 4H), 3.87 (dd, J=12.5, 4.6Hz, 1H), 3.29 (d, J=6.2 Hz, 2H), 2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)δ 162.18, 154.69, 144.99, 139.95, 137.75, 132.17, 131.73, 131.47,129.66, 126.63, 121.09, 120.65, 120.56, 116.82, 106.93, 106.65, 62.89,55.78, 53.31, 44.96, 28.72, 21.12. HRMS (ESI-TOF) calcd for C24H26N4O2[M+H]⁺ 403.2128, found: 403.2126.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-3-yl)propan-1-ol (ARN-28). To a flask equipped with a refluxcondenser and stirring bar were added2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-2-yl)propan-1-ol(0.1 g, 0.50 mmol), 2-butanone (10 mL) and1-(bromomethyl)-4-methylbenzene (0.111 g, 0.60 mmol). The resultingmixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 mL), extracted with CH₂Cl₂ (3×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the entitled free amine product as a brown gel (0.150 g, 75%);¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.43 (d, J=8.4 Hz, 1H),7.16-7.03 (m, 4H), 6.93-6.83 (m, 2H), 6.80-6.68 (m, 2H), 6.54 (d, J=8.4Hz, 1H), 4.94-4.77 (m, 2H), 4.26 (d, J=4.5 Hz, 1H), 4.08 (d, J=12.3 Hz,1H), 3.94 (dd, J=12.4, 4.8 Hz, 1H), 3.84 (s, 3H), 3.34-3.14 (m, 2H),2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.94, 154.71, 146.99, 139.87,137.72, 132.10, 131.54, 131.35, 129.68, 126.59, 126.42, 121.15, 120.74,110.36, 106.91, 106.88, 62.72, 59.04, 53.29, 44.94, 29.97, 21.12. HRMS(ESI-TOF) calcd for C24H26N4O2 [M+H]⁺ 403.2134, found: 403.2188.

3-(benzo[d]oxazol-2-yl)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propan-1-ol(ARN-37). To a flask equipped with a reflux condenser and stirring barwere added3-(benzo[d]oxazol-2-yl)-2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propan-1-ol(0.08 g, 0.26 mmol), 2-butanone (6 mL) and1-(bromomethyl)-4-methylbenzene (0.058 g, 0.31 mmol). The resultingmixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 mL), extracted with CH₂Cl₂ (3×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the entitled free amine product as a brown gel (65%); ¹H NMR(400 MHz, DMSO-d₆) δ 7.47-7.35 (m, 3H), 7.31-7.07 (m, 6H), 6.91-6.68 (m,3H), 5.12 (s, 2H), 4.75-4.66 (m, 1H), 3.73 (d, J=4.6 Hz, 1H), 3.58 (d,J=5.6 Hz, 1H), 3.10 (dd, J=15.6, 7.4 Hz, 1H), 2.90 (d, J=15.5 Hz, 1H),2.07 (s, 3H). ¹³C NMR (100 MHz, DMSO) δ 151.14, 150.27, 137.51, 133.34,130.51, 129.61, 128.42, 125.65, 122.98, 122.74, 119.05, 115.95, 110.32,110.04, 62.78, 52.23, 44.81, 31.15, 21.12.

(1R,2R)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-phenylpropane-1,3-diol(ARN-85). To a flask equipped with a reflux condenser and stirring barwere added(1R,2R)-2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-phenylpropane-1,3-diol (0.10 g, 0.35 mmol), 2-butanone (6 mL) and1-(bromomethyl)-4-methyl benzene (0.085 g, 0.45 mmol). The resultingmixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 mL), extracted with CH₂Cl₂ (3×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the entitled free amine product as a brown gel (68%); ¹H NMR(400 MHz, CDCl₃) δ 7.39 (d, J=7.5 Hz, 2H), 7.22-7.05 (m, 5H), 6.87 (ddt,J=22.7, 15.3, 7.6 Hz, 4H), 6.67 (d, J=7.6 Hz, 1H), 5.45 (d, J=4.8 Hz,1H), 4.94-4.75 (m, 3H), 4.54 (d, J=5.3 Hz, 1H), 4.36 (dd, J=11.7, 6.0Hz, 1H), 4.08 (dd, J=11.6, 6.3 Hz, 1H), 2.32 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 154.74, 141.90, 137.67, 131.56, 131.14, 129.63, 128.03, 127.01,126.30, 125.61, 121.50, 120.94, 107.05, 72.43, 62.63, 60.45, 44.81,21.10.

(1S,2S)-2-(3-((5-chlorobenzo[d]oxazol-2-yl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-phenylpropane-1,3-diol (ARN-99). To a flask equippedwith a reflux condenser and stirring bar were added(1S,2S)-2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-phenylpropane-1,3-diol(0.20 g, 0.7 mmol), 2-butanone (10 mL) and2-(bromomethyl)-5-chlorobenzo[d]oxazole (0.23 g, 0.9 mmol). Theresulting mixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 m), extracted with CH₂Cl₂ (3×25 m). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the entitled free amine product as a brown gel (53%); ¹H NMR (400MHz, CDCl₃) δ 7.64-7.21 (m, 5H), 7.18-6.65 (m, 7H), 5.50-5.32 (m, 2H),5.22-4.95 (m, 2H), 4.45 (s, 1H), 4.33-3.99 (m, 2H). ¹³C NMR (100 MHz,CDCl₃) δ 160.91, 149.44, 141.40, 130.35, 130.25, 128.12, 127.26, 126.13,125.69, 122.44, 121.49, 120.27, 111.66, 107.36, 72.03, 63.62, 62.63,60.07.

(1R,2R)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-methoxy-1-phenylpropan-1-ol(ARN-199). To a flask equipped with a reflux condenser and stirring barwere added(1R,2R)-2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-methoxy-1-phenylpropan-1-ol(0.08 g, 0.27 mmol), 2-butanone (6 mL) and1-(bromomethyl)-4-methylbenzene (0.086 g, 0.35 mmol). The resultingmixture was stirred at 75° C. for 8 h and then cooled to roomtemperature. After the evaporation of most 2-butanone under reducedpressure, the residue was sonicated with Et₂O (20 mL) and then thesupernatant was removed using pipette. This procedure was repeated threetimes and the remaining solid was mixed with saturated NaHCO₃ solution(25 m), extracted with CH₂Cl₂ (3×25 m). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the entitled free amine product as a brown gel (71%); [α]_(D)²⁰−9.0 (c 5.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.43 (d,J=8.4 Hz, 1H), 7.16-7.03 (m, 4H), 6.93-6.83 (m, 2H), 6.80-6.68 (m, 2H),6.54 (d, J=8.4 Hz, 1H), 4.94-4.77 (m, 2H), 4.26 (d, J=4.5 Hz, 1H), 4.08(d, J=12.3 Hz, 1H), 3.94 (dd, J=12.4, 4.8 Hz, 1H), 3.84 (s, 3H),3.34-3.14 (m, 2H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.94,154.71, 146.99, 139.87, 137.72, 132.10, 131.54, 131.35, 129.68, 126.59,126.42, 121.15, 120.74, 110.36, 106.91, 106.88, 62.72, 59.04, 53.29,44.94, 29.97, 21.12. HRMS (ESI-TOF) calcd for C25H27N3O2 [M+H]⁺402.2182, found: 402.2291.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-2-yl)propan-1-ol.Reaction of2-((2-aminophenyl)amino)-3-(6-methoxypyridin-2-yl)propan-1-ol (ProcedureE) yielded the title product. After the cyclization, the intermediate2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-2-yl)propan-1-olwas obtained as a dark brown gel (72%). ¹H NMR (400 MHz, DMSO-d6) δ 7.41(dd, J=8.2, 7.2 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.92-6.74(m, 2H), 6.63 (d, J=7.2 Hz, 1H), 6.48 (d, J=8.2 Hz, 1H), 6.30 (s, 2H),4.86 (s, 1H), 3.94 (dd, J=11.2, 7.1 Hz, 1H), 3.90-3.77 (br, 1H),3.86-3.81 (m, 1H), 3.73 (s, 3H), 3.40 (dd, J=14.4, 9.7 Hz, 1H), 3.23(dd, J=14.4, 5.5 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d6) δ 163.3, 156.1,155.4, 142.5, 139.6, 120.5, 118.3, 116.5, 114.9, 108.5, 62.5, 56.7,53.2, 36.6. After the alkylation of the intermediate above with4-methylbenzyl bromide, the desired final product was obtained as abrown gel (71%). ¹H NMR (400 MHz, CDCl₃) δ 7.31 (dd, J=8.3, 7.2 Hz, 1H),7.19-7.05 (m, 4H), 6.94-6.83 (m, 3H), 6.74 (dd, J=8.0, 1.5 Hz, 1H), 6.69(d, J=7.2 Hz, 1H), 6.46 (d, J=8.2 Hz, 1H), 4.89 (d, J=3.7 Hz, 2H), 4.77(q, J=7.4, 6.7 Hz, 1H), 4.12 (dd, J=12.3, 1.3 Hz, 1H), 3.96 (dd, J=12.4,4.6 Hz, 1H), 3.91 (s, 3H), 3.40 (dd, J=7.5, 2.1 Hz, 2H), 2.33 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 163.6, 156.0, 154.8, 138.8, 137.7, 132.1,131.6, 131.4, 129.6, 126.6, 121.0, 120.5, 116.7, 108.2, 107.2, 106.6,63.5, 57.3, 53.2, 45.0, 35.6, 21.1. MS (ESI) calcd for: C24H27N4O2(MH⁺): 403.2, found 403.2.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 4-methylbenzyl bromide (Procedure E) yielded thetitle product (75% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.12 (m,4H), 7.10 (d, J=8.2 Hz, 2H), 7.01 (d, J=7.8 Hz, 2H), 6.97-6.87 (m, 3H),6.80-6.73 (m, 2H), 4.89 (d, J=4.9 Hz, 2H), 4.33-4.19 (m, 1H), 4.06 (d,J=12.4 Hz, 1H), 3.94 (dd, J=12.4, 4.6 Hz, 1H), 3.41 (dd, J=13.4, 8.1 Hz,1H), 3.14 (dd, J=13.4, 7.3 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 154.8, 137.7, 135.9, 135.3, 132.1, 131.6, 131.6,129.7, 129.3, 129.0, 126.6, 121.1, 120.5, 106.9, 106.8, 62.6, 59.5,45.0, 33.3, 21.1, 21.0. MS (ESI) calcd for: C₂₅H₂₈N₃O (MH⁺): 386.2,found 386.3.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(pyridin-2-yl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(pyridin-2-yl)propan-1-ol,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (69% two steps). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d,J=4.9 Hz, 1H), 7.38 (td, J=7.6, 1.8 Hz, 1H), 7.21-7.02 (m, 6H),7.03-6.95 (m, 1H), 6.89-6.76 (m, 3H), 6.75-6.69 (m, 1H), 4.87 (d, J=4.1Hz, 2H), 4.73 (td, J=7.6, 4.4 Hz, 1H), 4.11 (dd, J=12.5, 1.1 Hz, 1H),3.94 (dd, J=12.4, 4.5 Hz, 1H), 3.60-3.41 (m, 2H), 2.33 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 158.6, 154.9, 149.3, 137.7, 136.2, 132.2, 131.5,131.3, 129.6, 126.6, 124.3, 121.5, 121.0, 120.4, 107.2, 106.5, 63.7,57.6, 44.9, 36.0, 21.1.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(2-methoxypyridin-4-yl)propan-1-ol.Cyclization of2-((2-aminophenyl)amino)-3-(2-methoxypyridin-4-yl)propan-1-ol, followedby alkylation with 4-methylbenzyl bromide (Procedure E) yielded thetitle product (60% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=5.2Hz, 1H), 7.20-7.03 (m, 6H), 6.94-6.87 (m, 2H), 6.80-6.74 (m, 2H),6.73-6.68 (m, 1H), 6.60 (s, 1H), 4.88 (d, J=8.2 Hz, 2H), 4.37-4.22 (m,1H), 4.08 (d, J=11.3 Hz, 1H), 3.93 (dd, J=12.5, 4.6 Hz, 1H), 3.84 (s,3H), 3.28 (dd, J=7.7, 3.4 Hz, 2H), 2.33 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 164.4, 154.7, 150.3, 146.7, 137.8, 132.0, 131.5, 131.4, 129.7,126.6, 121.1, 120.8, 118.2, 111.3, 106.8, 106.6, 63.2, 58.3, 53.3, 45.0,33.0, 21.1.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-phenylpropan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-phenylpropan-1-ol, followed byalkylation with 4-methylbenzyl bromide (Procedure E) yielded the titleproduct (63% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.04 (m, 10H),6.93-6.84 (m, 2H), 6.79-6.74 (m, 1H), 6.72-6.66 (m, 1H), 4.89 (d, J=5.6Hz, 2H), 4.29 (td, J=7.9, 4.7 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.95(dd, J=12.3, 4.6 Hz, 1H), 3.41 (dd, J=13.4, 7.7 Hz, 1H), 3.25 (dd,J=13.4, 7.8 Hz, 1H), 2.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.8,138.5, 137.8, 132.1, 131.6, 131.6, 129.7, 129.4, 128.3, 126.6, 126.4,121.0, 120.5, 106.8, 106.7, 62.9, 59.5, 45.0, 33.8, 21.1.

2-(2-imino-3-((6-methoxypyridin-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby the alkylation with 2-(bromomethyl)-6-methoxypyridine (Procedure E)yielded the title product as a brown gel (91% two steps). ¹H NMR (400MHz, CDCl₃) δ 7.50 (t, J=8.3 Hz, 1H), 7.12 (d, J=7.8 Hz, 2H), 7.03-6.88(m, 5H), 6.86-6.77 (m, 1H), 6.68 (dd, J=14.6, 7.8 Hz, 2H), 4.94 (s, 2H),4.35 (s, 1H), 4.07 (d, J=12.6 Hz, 1H), 4.00-3.90 (m, 1H), 3.88 (s, 3H),3.54-3.33 (m, 1H), 3.12 (dd, J=13.5, 7.4 Hz, 1H), 2.25 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 164.02, 154.57, 152.34, 139.41, 135.88, 135.07,131.49, 131.42, 129.18, 129.04, 121.34, 120.74, 113.78, 110.30, 107.32,107.14, 62.49, 59.70, 53.55, 47.03, 33.36, 21.00. MS (ESI) calcd for:C24H27N4O2 (MH⁺): 403.2, found 403.2.

2-(3-benzyl-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby the alkylation with benzylbromide (Procedure E) yielded the titleproduct as a brown gel (84% two steps). ¹H NMR (400 MHz, CDCl₃) δ7.39-7.28 (m, 3H), 7.21 (d, J=6.6 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.01(d, J=7.8 Hz, 2H), 6.99-6.87 (m, 3H), 6.79-6.72 (m, 2H), 4.93 (d, J=4.3Hz, 2H), 4.35-4.20 (m, 1H), 4.06 (d, J=12.5 Hz, 1H), 3.94 (dd, J=12.4,4.6 Hz, 1H), 3.42 (dd, J=13.4, 8.1 Hz, 1H), 3.15 (dd, J=13.4, 7.3 Hz,1H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.9, 135.9, 135.3,135.2, 131.6, 131.6, 129.3, 129.1, 129.0, 128.0, 126.6, 121.1, 120.5,106.9, 106.7, 62.6, 59.5, 45.2, 33.3, 21.0. MS (ESI) calcd for: C₂₄H₂N₃O(MH⁺): 372.2, found 372.2.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-(p-tolyl)butan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-4-(p-tolyl)butan-1-ol, followedby the alkylation with 4-methylbenzyl bromide (Procedure E) yielded thetitle product as a brown gel (>95% two steps). ¹H NMR (400 MHz, CDCl₃) δ7.19-7.06 (m, 8H), 6.98 (p, J=7.6, 7.1 Hz, 3H), 6.82 (d, J=7.3 Hz, 1H),6.73 (d, J=6.4 Hz, 1H), 4.88 (s, 2H), 4.13 (s, 1H), 4.07 (s, 2H), 2.75(ddd, J=14.3, 9.0, 5.9 Hz, 1H), 2.60 (dt, J=14.2, 7.7 Hz, 1H), 2.48 (td,J=13.7, 8.0 Hz, 1H), 2.34 (s, 3H), 2.33 (s, 3H), 2.31 (s, 1H). ¹³C NMR(100 MHz, CDCl₃) δ 154.9, 138.1, 137.7, 135.4, 132.2, 131.7, 131.7,129.7, 129.1, 128.3, 126.7, 121.1, 120.6, 107.1, 106.9, 63.2, 56.5,45.0, 31.8, 28.9, 21.1, 21.0.

2-(2-imino-5-methyl-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-amino-4-methylphenyl)amino)-3-(p-tolyl)propan-1-ol,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (77% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (dd,J=8.2, 2.7 Hz, 4H), 7.10 (d, J=8.0 Hz, 2H), 7.04 (d, J=7.7 Hz, 2H), 6.76(d, J=7.3 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.61 (s, 1H), 4.87 (d, J=4.4Hz, 2H), 4.23 (q, J=7.3, 6.8 Hz, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.93 (dd,J=12.3, 4.6 Hz, 1H), 3.43 (dd, J=13.4, 8.3 Hz, 1H), 3.11 (dd, J=13.4,7.1 Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 155.0, 137.7, 135.8, 135.4, 132.3, 131.8, 130.4, 129.7, 129.5,129.3, 129.1, 126.5, 121.5, 107.5, 106.7, 62.5, 59.5, 44.9, 33.4, 21.3,21.1, 21.1.

Synthesis with General Procedure (E).

2-(3-(3,5-dimethylbenzyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol

Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 3,5-dimethylbenzyl bromide (Procedure E) yielded thetitle product (94% two steps) as a brown gel. ¹H NMR (400 MHz, CDCl₃) δ7.15 (d, J=7.7 Hz, 2H), 7.01 (d, J=7.8 Hz, 2H), 6.96-6.87 (m, 3H), 6.83(s, 2H), 6.83-6.76 (m, 1H), 6.76-6.69 (m, 1H), 4.85 (d, J=3.4 Hz, 2H),4.25 (m, 1H), 4.06 (d, J=12.5 Hz, 1H), 3.93 (dd, J=12.4, 4.6 Hz, 1H)3.41 (dd, J=13.4, 8.1 Hz, 1H), 3.14 (dd, J=13.4, 7.2 Hz, 1H), 2.30 (s,6H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.86, 138.71, 135.86,135.35, 135.13, 131.73, 131.62, 129.68, 129.23, 129.05, 124.37, 121.04,120.52, 106.88, 106.74, 62.64, 59.58, 45.32, 33.36, 21.34, 21.01.

2-(2-imino-3-((2-methoxypyridin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 4-(bromomethyl)-2-methoxypyridine (Procedure E)yielded the title product (93% two steps) as a brown gel. ¹H NMR (400MHz, CDCl₃) δ 8.12 (d, J=5.3 Hz, 1H), 7.13 (d, J=7.6 Hz, 2H), 7.07-6.87(m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.70 (d, J=7.1 Hz, 1H), 6.50 (s, 1H),4.88 (d, J=7.5 Hz, 2H), 4.38-4.23 (m, 1H), 4.11-4.04 (m, 1H), 3.96 (dd,J=12.4, 4.9 Hz, 1H), 3.92 (s, 3H), 3.39 (dd, J=13.5, 7.9 Hz, 1H), 3.17(dd, J=13.5, 7.6 Hz, 1H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ164.80, 154.45, 147.66, 146.98, 135.98, 135.02, 129.41, 129.18, 129.11,128.69, 121.55, 120.78, 114.65, 108.46, 107.31, 106.70, 62.68, 59.62,53.52, 44.05, 33.30, 21.02.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-phenylethanol.Cyclization of 2-((2-aminophenyl)amino)-2-phenylethanol, followed byalkylation with 4-methylbenzyl bromide (Procedure E) yielded the titleproduct (91% two steps) as a brown gel. ¹H NMR (400 MHz, CDCl₃) δ 7.32(d, J=5.7 Hz, 4H), 7.29-7.21 (m, 2H), 7.16 (s, 3H), 6.99-6.69 (m, 4H),5.38-5.27 (m, 1H), 4.95 (s, 2H), 4.46-4.31 (m, 2H), 2.34 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 155.27, 137.79, 137.47, 132.11, 131.80, 131.72,129.74, 128.59, 127.49, 127.03, 126.62, 121.24, 121.03, 107.93, 106.78,63.68, 61.68, 45.14, 21.12.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-(p-tolyl)ethanol.Cyclization of 2-((2-aminophenyl)amino)-2-(p-tolyl)ethan-1-ol, followedby alkylation with 4-methylbenzyl bromide (Procedure E) yielded thetitle product (46% two steps) as a brown gel. ¹H NMR (400 MHz, CDCl₃) δ7.23-7.09 (m, 7H), 6.99-6.87 (m, 2H), 6.83 (d, J=7.0 Hz, 1H), 6.73 (d,J=7.3 Hz, 1H), 5.37-5.25 (m, 1H), 4.96 (s, 2H), 4.46-4.27 (m, 2H), 2.34(s, 3H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.23, 137.77,137.13, 134.35, 132.11, 131.79, 131.74, 129.73, 129.30, 126.91, 126.62,121.25, 120.98, 107.97, 106.76, 63.74, 61.44, 45.14, 21.11, 21.10.

2-(2-imino-3-((2-methoxypyridin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 4-(bromomethyl)-2-methoxypyridine (Procedure E)yielded the title product (79% two steps) as a brown foam. ¹H NMR (400MHz, CDCl₃) δ 8.12 (d, J=5.2 Hz, 1H), 7.20-6.32 (m, 11H), 5.06-4.78 (m,2H), 4.41-4.27 (m, 1H), 4.13-3.83 (m, 5H), 3.38 (dd, J=13.5, 7.8 Hz,1H), 3.18 (dd, J=13.5, 7.7 Hz, 1H), 2.26 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 164.75, 154.54, 147.56, 147.21, 135.95, 134.98, 131.10, 129.26,129.14, 129.11, 121.44, 120.72, 114.72, 108.44, 107.44, 106.69, 62.59,59.48, 53.51, 43.91, 33.37, 21.10, 21.03, 21.00.

2-(2-imino-3-((6-methoxypyridin-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 2-(bromomethyl)-6-methoxypyridine (Procedure E)yielded the title product (79% two steps) as a brown foam. ¹H NMR (400MHz, CDCl₃) δ 7.58-7.42 (m, 1H), 7.13 (d, J=7.8 Hz, 2H), 7.04-6.59 (m,8H), 4.92 (s, 2H), 4.35-4.23 (m, 1H), 4.08-3.87 (m, 5H), 3.42 (dd,J=13.4, 8.2 Hz, 1H), 3.11 (dd, J=13.4, 7.2 Hz, 1H), 2.25 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 164.03, 154.72, 152.43, 139.40, 135.87, 135.16,131.53, 129.31, 129.21, 129.04, 121.24, 120.61, 113.70, 110.26, 107.12,106.97, 62.49, 59.61, 53.55, 46.98, 33.34, 21.00.

2-(3-(3,5-dimethylbenzyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-(p-tolyl)ethanol.Cyclization of 2-((2-aminophenyl)amino)-2-(p-tolyl)ethan-1-ol, followedby alkylation with 1-(bromomethyl)-3,5-dimethylbenzene (Procedure E)yielded the title product (76% two steps) as a brown foam. ¹H NMR (400MHz, CDCl₃) δ 7.22 (d, J=7.8 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 7.00-6.80(m, 6H), 6.76 (d, J=7.4 Hz, 1H), 5.35-5.26 (m, 1H), 4.91 (s, 2H),4.52-4.16 (m, 2H), 2.31 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 155.37,138.73, 137.12, 135.14, 134.46, 131.92, 131.81, 129.66, 129.30, 126.94,124.37, 121.20, 120.97, 107.89, 106.73, 63.74, 61.37, 45.27, 21.36,21.11.

2-(2-imino-3-(thiophen-3-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 3-(bromomethyl)thiophene (Procedure E) yielded thetitle product (81% two steps) as a brown foam. ¹H NMR (400 MHz, CDCl₃) δ7.38-7.29 (m, 1H), 7.13 (d, J=7.6 Hz, 2H), 7.09-6.69 (m, 8H), 4.92 (s,2H), 4.31-4.20 (m, 1H), 4.06 (d, J=12.4 Hz, 1H), 3.94 (dd, J=12.4, 4.6Hz, 1H), 3.41 (dd, J=13.4, 8.1 Hz, 1H), 3.14 (dd, J=13.4, 7.3 Hz, 1H),2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.61, 136.05, 135.88, 135.24,131.58, 131.28, 129.24, 129.06, 127.18, 126.23, 122.26, 121.13, 120.53,106.99, 106.64, 62.63, 59.48, 41.00, 33.33, 21.02.

2-(2-imino-3-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-toyl)propan-1-ol.Cyclization of 2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol, followedby alkylation with 2-(bromomethyl)-5-(trifluoromethyl)furan (ProcedureE) yielded the title product (42% two steps) as a brown foam. ¹H NMR(400 MHz, CDCl₃) δ 7.09 (d, J=7.6 Hz, 2H), 7.05-6.68 (m, 8H), 6.26 (d,J=4.0 Hz, 1H), 4.91 (s, 2H), 4.30-4.17 (m, 1H), 4.08-3.90 (m, 2H), 3.37(dd, J=13.5, 7.9 Hz, 1H), 3.13 (dd, J=13.5, 7.5 Hz, 1H), 2.24 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 154.17, 151.51, 135.94, 135.05, 131.52,130.77, 129.33, 129.14, 129.05, 121.55, 120.70, 119.20 (q), 112.58,109.02, 107.26, 106.63, 62.49, 59.55, 38.44, 33.31, 20.97.

1-(1-methoxy-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-imine.Cyclization of N¹-(1-methoxy-3-(p-tolyl)propan-2-yl)benzene-1,2-diamine,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (74% two steps) as a brown foam. ¹H NMR (400 MHz,CDCl₃) δ 7.20-6.78 (m, 11H), 6.69 (d, J=7.5 Hz, 1H), 4.91 (m, 3H), 4.50(br, 1H), 3.98 (m, J=8.3 Hz, 1H), 3.80 (dd, J=9.9, 4.9 Hz, 1H), 3.37 (s,4H), 3.23 (dd, J=13.9, 6.5 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 154.79, 137.08, 135.83, 134.75, 132.93, 131.67,129.38, 129.07, 128.96, 126.66, 120.33, 120.17, 106.56, 72.37, 59.04,55.86, 44.73, 34.27, 21.12, 21.10.

(R)-2-hydroxy-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Cyclization of(R)—N-(2-((2-aminophenyl)amino)-3-(p-tolyl)propyl)-2-hydroxyacetamide,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (76% two steps). [α]_(D) ²⁰ 85.58 (c 0.25, DCM). H NMR(400 MHz, CDCl₃) δ 7.35 (br s, 1H), 7.18-7.03 (m, 3H), 7.03-6.96 (m,2H), 6.95 (s, 4H), 6.91-6.79 (m, 2H), 6.75 (d, J=7.6 Hz, 1H), 4.88 (d,J=16.8 Hz, 1H), 4.78 (d, J=17.0 Hz, 1H), 4.16-4.02 (m, 1H), 4.01-3.89(m, 2H), 3.74 (br s, 1H), 3.56-3.32 (m, 1H), 3.14 (dd, J=14.2, 5.8 Hz,1H), 2.96 (br s, 2H), 2.31 (s, 3H), 2.25 (s, 3H).

(S)-2-hydroxy-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Cyclization of(S)—N-(2-((2-aminophenyl)amino)-3-(p-tolyl)propyl)-2-hydroxyacetamide,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (50% two steps). [α]_(D) ²⁰−39.19 (c 0.25, DCM). H NMR(400 MHz, CDCl₃) δ 7.30 (br s, 1H), 7.25-7.19 (m, 1H), 7.13-7.02 (m,2H), 6.96 (d, J=7.7 Hz, 2H), 6.83 (d, J=7.7 Hz, 2H), 4.59 (s, 1H), 4.42(br s, 1H), 3.95 (s, 1H), 3.83 (d, J=3.8 Hz, 2H), 3.80-3.60 (m, 1H),3.30 (dd, J=11.8 Hz, 1H), 3.12 (dd, J=13.9, 5.2 Hz, 1H), 2.23 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 174.3, 155.0, 141.5, 136.7, 133.8, 129.5,128.6, 122.0, 120.1, 116.3, 110.2, 61.3, 57.2, 40.9, 36.3, 21.1.

Synthesis with General Procedure (F).

6-(3-hydroxy-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)pyridin-2(1H)-one

Reaction of2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-2-yl)propan-1-ol(Procedure F) yielded the title product as a brown foam (0.0451g, >95%). ¹H NMR (400 MHz, CDCl₃) δ 7.22 (dd, J=9.1, 6.8 Hz, 1H),7.18-7.04 (m, 6H), 6.99-6.86 (m, 2H), 6.78 (d, J=7.3 Hz, 1H), 6.35 (d,J=9.5 Hz, 1H), 6.08 (d, J=6.8 Hz, 1H), 4.88 (d, J=9.0 Hz, 2H), 4.77 (s,1H), 4.13 (d, J=12.9 Hz, 1H), 4.01 (dd, J=12.6, 4.6 Hz, 1H), 3.43-3.20(m, 2H), 2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 154.6, 145.6,141.6, 137.8, 132.0, 131.4, 129.7, 126.6, 121.3, 120.9, 117.8, 107.7,107.6, 106.8, 63.2, 56.2, 45.0, 31.4, 21.1. MS (ESI) calcd for:C₂₃H₂₅N₄O₂ (MH⁺): 389.2, found 389.2.

4-((3-(1-hydroxy-3-(p-tolyl)propan-2-yl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-2(1H)-one.Reaction of2-(2-imino-3-((2-methoxypyridin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imi-dazol-1-yl)-3-(p-tolyl)propan-1-ol(Procedure F) yielded the title product as a red powder (77%). ¹H NMR(400 MHz, CDCl₃) δ 7.24-6.88 (m, 9H), 6.82 (d, J=7.6 Hz, 1H), 6.69 (d,J=7.5 Hz, 1H), 6.26 (s, 1H), 6.02 (d, J=6.5 Hz, 1H), 4.74 (s, 2H),4.44-4.23 (m, 1H), 4.09-3.88 (m, 2H), 3.36 (dd, J=13.5, 7.8 Hz, 1H),3.21-3.05 (m, 1H), 2.22 (d, J=14.5 Hz, 4H). ¹³C NMR (100 MHz, CDCl₃) δ164.79, 154.37, 150.40, 136.00, 135.23, 134.91, 130.95, 129.27, 129.14,129.11, 128.72, 121.64, 120.91, 116.84, 106.82, 105.17, 62.24, 59.59,44.13, 33.48, 21.02.

6-((3-(1-hydroxy-3-(p-tolyl)propan-2-yl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-2(1H)-one.Reaction of2-(2-imino-3-((6-methoxypyridin-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imi-dazol-1-yl)-3-(p-tolyl)propan-1-ol(Procedure F) yielded the title product as a pale brown powder (70%). ¹HNMR (400 MHz, CDCl₃) δ 7.30 (t, J=8.0 Hz, 1H), 6.97 (m, 12H), 6.45 (d,J=9.1 Hz, 1H), 5.91 (d, J=6.9 Hz, 1H), 4.92 (s, 2H), 4.42 (s, 1H),4.17-3.93 (m, 2H), 3.33 (dd, J=13.7, 7.3 Hz, 1H), 3.16 (dd, J=13.7, 8.0Hz, 1H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.38, 154.33,143.68, 141.35, 136.06, 134.65, 130.83, 129.10, 129.01, 121.71, 121.10,118.87, 110.00, 108.04, 106.98, 104.66, 62.40, 59.68, 33.56, 21.02.

Synthesis with General Procedure (G).

tert-butyl-(1-(1-benzamido-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate

Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith benzoyl chloride (Procedure G) yielded the title product (88%) as awhite foam. ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 7.83 (d, J=7.6 Hz, 2H),7.39 (t, J=7.4 Hz, 1H), 7.30 (t, J=7.6 Hz, 2H), 7.20-7.11 (m, 1H), 7.07(t, J=7.7 Hz, 1H), 7.03-6.82 (m, 10H), 5.17 (dd, J=27.4, 15.7 Hz, 2H),5.08 (s, 1H), 4.60 (s, 1H), 3.79 (s, 1H), 3.36 (s, 1H), 3.22 (dd,J=14.0, 6.7 Hz, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 1.53 (s, 9H). ¹³C NMR(100 MHz, CDCl3, 50° C.) δ 167.4, 159.3, 153.2, 137.4, 136.5, 134.1,132.0, 130.9, 130.4, 129.3, 128.7, 128.1, 127.3, 127.0, 123.0, 110.4,78.3, 57.3, 46.7, 41.9, 36.9, 28.6, 20.9, 20.9.

tert-butyl-(1-(1-(cyclopropanecarboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith cyclopropanecarbonyl chloride (Procedure G) yielded the titleproduct (54%) as a white foam. ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 7.13(t, J=7.9 Hz, 1H), 7.07 (d, J=6.9 Hz, 3H), 7.02 (d, J=8.1 Hz, 2H), 6.94(q, J=8.1 Hz, 6H), 5.18 (s, 2H), 4.91 (s, 1H), 4.27 (d, J=15.0 Hz, 1H),3.66 (d, J=15.2 Hz, 1H), 3.33 (s, 1H), 3.13 (dd, J=14.1, 6.4 Hz, 1H),2.30 (s, 3H), 2.24 (s, 3H), 1.51 (s, 9H), 1.38-1.29 (m, 1H), 0.73 (s,2H), 0.52 (s, 2H). ¹³C NMR (100 MHz, CDCl3, 50° C.) δ 174.0, 137.5,136.3, 132.0, 130.3, 129.3, 129.2, 128.7, 127.2, 122.9, 122.8, 110.3,78.2, 57.6, 46.9, 41.6, 28.6, 20.9, 20.9, 14.4, 6.7, 6.4.

tert-butyl-(1-(4-methylbenzyl)-3-(1-(2-phenylacetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-phenylacetyl chloride (Procedure G) yielded the title product(30%) as a white foam. ¹H NMR (400 MHz, CDOD₃, 50° C.) δ 7.46-6.76 (m,18H), 5.32-5.09 (m, 2H), 4.95 (s, 1H), 4.07 (s, 1H), 3.77 (s, 1H),3.50-3.35 (m, 1H), 3.32 (s, 2H), 3.12 (s, 1H), 2.25 (s, 3H), 2.18 (s,3H), 1.44 (s, 9H).

tert-butyl-(1-(1-(2-(4-methoxyphenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(4-methoxyphenyl)acetyl chloride (Procedure G) yielded the titleproduct (54%) as a white gel. ¹H NMR (400 MHz, CDCl₃, 50° C.) δ7.18-6.98 (m, 6H), 6.97-6.76 (m, 8H), 6.58 (d, J=8.2 Hz, 2H), 5.14 (q,J=16.0 Hz, 2H), 4.85 (s, 1H), 4.25 (s, 1H), 3.72 (s, 3H), 3.62 (s, 1H),3.36 (s, 1H), 3.27 (s, 2H), 3.08 (dd, J=14.0, 6.3 Hz, 1H), 2.30 (s, 3H),2.24 (s, 3H), 1.49 (s, 9H).

tert-butyl-1-(1-((E)-but-2-enamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith crotonoyl chloride (90% trans) (Procedure G) yielded the titleproduct (71%) as a white gel with a small amount of cis product. ¹H NMR(400 MHz, CDCl₃, 50° C.) δ 7.22-6.84 (m, 12H), 6.78-6.49 (m, 1H), 5.75(dd, J=15.4, 1.8 Hz, 1H), 5.18 (s, 2H), 4.92 (d, J=9.3 Hz, 1H), 4.37 (s,1H), 3.67 (d, J=14.6 Hz, 1H), 3.39-3.25 (m, 1H), 3.14 (dd, J=14.0, 6.6Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.75 (dd, J=6.9, 1.8 Hz, 3H), 1.51(s, 9H).

Synthesis with General Procedure (H).

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)propionamide

Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-propionamido-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (63%) as a yellow gel. ¹H NMR(400 MHz, CDCl₃) δ 7.25-6.61 (m, 12H), 5.46-4.80 (br, 1H), 4.88 (dd,J=24.7, 17.7 Hz, 2H), 4.55 (s, 2H), 4.05 (s, 1H), 3.69 (s, 1H), 3.44 (s,1H), 3.14 (d, J=10.7 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 2.12 (q, J=7.6Hz, 2H), 1.04 (t, J=7.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 174.4,154.1, 137.7, 136.0, 134.2, 131.0, 129.6, 129.1, 128.7, 126.4, 121.7,107.8, 56.6, 45.0, 41.6, 34.8, 29.6, 21.1, 21.0, 9.8.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)benzamide.Reaction oftert-butyl-(1-(1-benzamido-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (93%) as a yellow gel. ¹H NMR(400 MHz, CDCl₃) δ 7.84 (s, 2H), 7.45 (t, J=7.3 Hz, 1H), 7.41-7.29 (m,2H), 7.20-6.77 (m, 11H), 6.73 (d, J=7.5 Hz, 1H), 5.02-4.49 (br, 1H),4.88 (dd, J=20.8, 17.2 Hz, 2H), 4.34 (s, 1H), 3.71 (s, 1H), 3.58 (s,1H), 3.23 (dd, J=13.8, 6.2 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 167.5, 155.3, 137.5, 136.0, 132.1, 131.4, 131.1,129.6, 129.4, 129.1, 128.9, 128.3, 127.3, 126.4, 121.1, 120.6, 106.7,55.9, 44.7, 43.3, 28.6, 21.1, 21.0.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)cyclopropanecarboxamide.Reaction oftert-butyl-(1-(1-(cyclopropanecarboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (94%) as a yellow gel. ¹H NMR(400 MHz, CDCl₃) δ 7.22-6.63 (m, 12H), 5.50-4.92 (br, 1H), 4.86 (s, 2H),3.98 (s, 1H), 3.75 (s, 1H), 3.46 (s, 1H), 3.13 (dd, J=13.9, 5.7 Hz, 1H),2.32 (s, 3H), 2.23 (s, 3H), 1.42-1.32 (m, 1H), 0.88 (s, 2H), 0.65 (d,J=5.2 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 174.0, 154.5, 137.4, 135.8,131.1, 129.5, 129.0, 128.7, 126.2, 121.3, 107.3, 56.2, 44.7, 41.8, 34.6,21.0, 21.0, 14.6, 7.0, 6.8.

2,2,2-trifluoro-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-(2,2,2-trifluoroacetamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (84%) as a yellow gel. ¹H NMR(400 MHz, CDCl₃) δ 7.15 (d, J=7.8 Hz, 2H), 7.03 (d, J=7.7 Hz, 2H),6.99-6.85 (m, 7H), 6.85-6.71 (m, 2H), 4.88 (d, J=4.8 Hz, 2H), 4.64 (s,1H), 4.21 (dd, J=14.4, 6.0 Hz, 1H), 3.46 (dt, J=13.9, 10.1 Hz, 2H), 3.16(dd, J=13.8, 6.6 Hz, 1H), 2.35 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 157.6 (q, J=36.5 Hz), 154.9, 137.9, 136.3, 134.0, 131.8, 131.3,129.7, 129.2, 128.8, 126.4, 121.3, 121.0, 107.1, 55.7, 44.9, 43.0, 33.6,21.1, 21.0.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-phenylacetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-phenylacetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (20% over two steps combinedwith the synthesis oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-phenylacetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate)as a yellow gel. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.15 (m, 3H), 7.13-7.02(m, 5H), 6.93 (s, 9H), 6.71 (d, J=7.2 Hz, 1H), 5.04-4.46 (m, 3H), 3.98(s, 1H), 3.64 (d, J=13.5 Hz, 1H), 3.46 (s, 2H), 3.44-3.29 (m, 1H), 3.06(dd, J=13.9, 6.0 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 171.5, 154.4, 137.5, 135.9, 135.0, 132.2, 131.3, 129.6, 129.4,129.1, 128.9, 128.8, 128.7, 128.6, 126.9, 126.5, 121.1, 120.6, 106.7,55.7, 44.8, 43.8, 41.7, 28.6, 21.1, 21.0.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)formamide.Reaction oftert-butyl-(1-(1-formamido-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (>95%) as a yellow gel. ¹H NMR(400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.10 (d, J=7.7 Hz, 2H), 7.06-6.88 (m,9H), 6.73 (d, J=7.5 Hz, 1H), 5.00-4.52 (m, 4H), 4.09 (s, 1H), 3.67 (d,J=14.2 Hz, 1H), 3.54-3.37 (m, 1H), 3.12 (dd, J=13.9, 5.8 Hz, 1H), 2.32(s, 3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 161.5, 154.8, 137.6,136.1, 134.3, 132.1, 131.3, 129.6, 129.1, 128.8, 126.4, 121.1, 120.8,106.9, 55.8, 44.8, 40.4, 34.5, 21.1, 21.1.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(4-methoxyphenyl)acetamide.Reaction oftert-butyl-(1-(1-(2-(4-methoxyphenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (53% over two steps combinedwith the synthesis oftert-butyl-(1-(1-(2-(4-methoxyphenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate)as a yellow gel. ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J=7.8 Hz, 3H),7.02-6.76 (m, 10H), 6.70 (d, J=8.7 Hz, 3H), 4.87-4.73 (m, 2H), 4.68 (s,1H), 3.94 (s, 1H), 3.75 (s, 3H), 3.71-3.61 (m, 1H), 3.42 (s, 1H), 3.39(s, 2H), 3.05 (dd, J=13.9, 6.1 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 171.9, 158.5, 137.5, 135.9, 132.4, 131.4, 130.4,129.6, 129.1, 128.8, 126.9, 126.5, 120.8, 120.4, 114.1, 106.5, 55.4,55.2, 44.6, 42.9, 41.6, 34.7, 21.1, 21.0.

(E)-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)but-2-enamide.Reaction oftert-butyl-1-(1-((E)-but-2-enamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product (57% over two steps combinedwith the synthesis oftert-butyl-1-(1-((E)-but-2-enamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate)as a yellow gel. ¹H NMR (400 MHz, CDCl₃) δ 7.11 (dd, J=8.0, 5.0 Hz, 3H),7.06-6.82 (m, 8H), 6.76 (dd, J=15.1, 7.0 Hz, 1H), 6.71 (d, J=7.4 Hz,1H), 5.76 (d, J=14.6 Hz, 1H), 4.95-4.77 (m, 2H), 4.71 (s, 1H), 4.10 (s,1H), 3.68 (s, 1H), 3.50 (s, 1H), 3.14 (dd, J=14.0, 6.2 Hz, 1H), 2.33 (s,3H), 2.23 (s, 3H), 1.80 (d, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ166.3, 155.2, 139.0, 137.5, 135.9, 134.6, 132.3, 131.4, 129.6, 129.1,128.8, 126.4, 125.5, 120.9, 120.5, 106.6, 55.8, 44.7, 42.2, 34.4, 21.1,21.0, 17.7.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(pyridin-4-yl)acetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyridin-4-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (63% over twosteps combined with the synthesis oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyridin-4-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate).¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=6.2 Hz, 2H), 7.12 (d, J=7.7 Hz,2H), 7.06 (d, J=5.1 Hz, 2H), 6.99 (d, J=7.2 Hz, 2H), 6.94 (s, 4H),6.91-6.83 (m, 2H), 6.75-6.67 (m, 1H), 4.79 (dd, J=22.5, 16.8 Hz, 2H),4.64 (s, 1H), 4.06 (s, 1H), 3.55 (d, J=13.4 Hz, 1H), 3.45 (s, 3H), 3.06(dd, J=13.8, 6.2 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 169.5, 155.0, 149.9, 144.1, 137.6, 136.0, 134.4, 132.3, 131.3,129.6, 129.1, 128.8, 126.5, 124.5, 120.9, 120.5, 107.4, 106.6, 55.4,44.6, 43.0, 42.4, 34.3, 21.1, 21.0.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(pyridin-3-yl)acetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyridin-3-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (61% over twosteps combined with the synthesis oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyridin-3-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate).¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.8 Hz, 1H), 8.41 (s, 1H), 7.49 (d,J=7.8 Hz, 1H), 7.12 (dd, J=7.7, 4.7 Hz, 3H), 7.04-6.77 (m, 9H),6.74-6.63 (m, 1H), 4.94-4.74 (m, 2H), 4.64 (s, 1H), 4.05 (s, 1H), 3.54(d, J=14.2 Hz, 1H), 3.46 (s, 2H), 3.43-3.35 (m, 1H), 3.18-2.97 (m, 1H),2.33 (s, 3H), 2.22 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 155.1,150.6, 148.4, 137.7, 137.0, 136.1, 132.4, 131.5, 131.1, 129.7, 129.2,128.9, 126.6, 123.6, 121.1, 120.6, 106.8, 77.2, 55.7, 44.8, 42.7, 41.0,28.7, 21.3, 21.2.

2-(4-aminophenyl)-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction oftert-butyl-1-(1-(2-(4-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow foam (90%). ¹H NMR(400 MHz, CDCl₃) δ 7.11 (d, J=7.7 Hz, 2H), 7.03-6.84 (m, 8H), 6.78 (d,J=7.8 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.46 (d, J=8.3 Hz, 2H), 4.80 (dd,J=22.0, 16.8 Hz, 2H), 3.92 (s, 1H), 3.82-3.51 (m, 3H), 3.41 (s, 1H),3.32 (s, 2H), 3.06 (dd, J=13.9, 6.0 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 172.3, 154.4, 145.3, 137.4, 135.9, 134.5,132.4, 131.3, 130.3, 129.5, 129.1, 128.8, 126.5, 124.6, 120.9, 120.5,115.3, 106.6, 55.5, 44.7, 42.9, 41.5, 34.6, 21.1, 21.0.

2-(2-aminophenyl)-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction oftert-butyl-1-(1-(2-(2-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow foam (80%). ¹H NMR(400 MHz, CDCl₃) δ 7.12 (d, J=7.6 Hz, 2H), 7.02 (td, J=7.7, 1.6 Hz, 2H),7.00-6.83 (m, 9H), 6.71 (d, J=6.6 Hz, 1H), 6.64 (t, J=7.4 Hz, 1H), 6.55(d, J=7.8 Hz, 1H), 5.00-4.65 (br, 1H), 4.78 (dd, J=25.2, 17.0 Hz, 2H),4.50-3.80 (br, 4H), 3.59 (d, J=13.8 Hz, 1H), 3.38 (s, 3H), 3.08 (dd,J=13.9, 6.2 Hz, 1H), 2.34 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 171.6, 154.7, 145.8, 137.6, 135.9, 134.4, 132.3, 131.3, 131.0,129.6, 129.1, 128.8, 128.2, 126.5, 120.9, 120.4, 118.5, 116.1, 106.7,55.6, 44.7, 41.9, 40.9, 34.5, 21.1, 21.1.

2-(3-aminophenyl)-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction oftert-butyl-1-(1-(2-(3-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow foam (95%). ¹H NMR(400 MHz, CDCl₃) δ 7.10 (d, J=7.7 Hz, 3H), 7.02-6.82 (m, 9H), 6.70 (d,J=7.5 Hz, 1H), 6.48 (dd, J=8.0, 1.4 Hz, 1H), 6.41 (d, J=6.6 Hz, 1H),6.29 (s, 1H), 4.90-4.55 (br, 1H), 4.82 (dd, J=30.3, 16.4 Hz, 2H), 3.95(s, 1H), 3.67 (d, J=10.8 Hz, 1H), 3.42 (s, 1H), 3.34 (s, 2H), 3.06 (dd,J=13.9, 5.8 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 171.6, 154.3, 146.8, 137.5, 135.9, 134.5, 132.4, 131.3, 129.6,129.5, 129.1, 128.8, 126.5, 121.0, 120.4, 119.5, 115.9, 113.7, 106.7,55.7, 44.7, 43.8, 41.4, 34.7, 21.1, 21.1.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(pyridin-2-yl)acetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyridin-2-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a white gel (93%). ¹H NMR(400 MHz, CDCl₃) δ 8.23 (d, J=4.6 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H),7.19-7.05 (m, 3H), 7.05-6.90 (m, 8H), 6.83 (s, 2H), 6.64 (d, J=5.2 Hz,1H), 4.83 (dd, J=26.1, 17.0 Hz, 2H), 4.76 (s, 1H), 3.88 (d, J=54.4 Hz,3H), 3.62 (dd, J=20.5, 15.4 Hz, 2H), 3.51-3.31 (m, 1H), 3.06 (dd,J=13.9, 5.8 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 169.7, 155.4, 148.9, 137.3, 136.7, 135.8, 134.6, 132.6, 131.4,129.5, 129.0, 128.8, 126.6, 123.8, 121.7, 120.6, 120.1, 106.4, 55.4,45.4, 44.6, 41.1, 29.7, 21.1, 21.0.

2-amino-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction oftert-butyl-(1-(1-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (51%). ¹H NMR(400 MHz, CD₃OD) δ 7.42 (s, 1H), 7.19-6.56 (m, 11H), 4.99 (d, J=15.9 Hz,2H), 3.85 (s, 2H), 3.60 (s, 1H), 3.47-3.33 (m, 1H), 3.13 (s, 3H), 2.28(s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 175.8, 156.9, 138.2,137.1, 135.7, 134.4, 132.7, 130.2, 130.0, 130.0, 127.8, 122.2, 122.0,110.9, 108.9, 57.1, 45.3, 45.1, 41.6, 35.9, 21.2, 21.1.

4-hydroxy-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)butanamide.Reaction oftert-butyl-(1-(1-(4-hydroxybutanamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow foam (>95%). ¹H NMR(400 MHz, CDCl₃, 50° C.) δ 8.24-7.38 (m, 2H), 7.15 (t, J=7.7 Hz, 1H),7.04 (d, J=7.8 Hz, 2H), 6.98 (d, J=7.8 Hz, 1H), 6.90 (d, J=7.9 Hz, 2H),6.84 (d, J=7.9 Hz, 2H), 6.77 (d, J=7.4 Hz, 2H), 5.57 (s, 2H), 5.24-4.97(m, 3H), 4.23 (dd, J=12.5, 5.6 Hz, 1H), 3.62 (dd, J=13.9, 4.5 Hz, 1H),3.44 (t, J=5.7 Hz, 2H), 3.35 (dd, J=14.5, 10.5 Hz, 1H), 3.20 (dd,J=14.3, 5.3 Hz, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 2.22-2.12 (m, 2H), 1.66(h, J=6.7 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃, 50° C.) δ 174.1, 161.8,144.2, 138.1, 136.4, 130.4, 129.7, 129.2, 128.5, 126.3, 123.3, 61.7,45.9, 40.8, 40.7, 35.2, 33.4, 28.1, 20.9, 20.9.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(pyrimidin-2-yl)acetamide.Reaction oftert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyrimidin-2-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a white foam (77%). ¹H NMR(400 MHz, CDCl₃) δ 8.41 (d, J=4.8 Hz, 2H), 7.22-6.75 (m, 12H), 6.66 (d,J=4.8 Hz, 1H), 4.84 (dd, J=27.9, 16.7 Hz, 2H), 4.02 (s, 2H), 3.85 (s,3H), 3.44 (s, 1H), 3.10 (dd, J=13.9, 5.9 Hz, 1H), 2.31 (s, 3H), 2.22 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 165.3, 156.9, 137.4, 135.9,134.5, 132.6, 131.4, 129.5, 129.4, 129.0, 128.8, 126.6, 120.7, 120.2,118.9, 110.0, 106.4, 55.6, 46.7, 44.6, 41.2, 34.8, 21.1, 21.0.

(S)-3,3,3-trifluoro-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)propenamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-(3,3,3-trifluoropropanamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (76%). [□]_(D)²⁰−81.694 (c 1.028, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.14 (d, J=7.7 Hz,2H), 7.08-6.79 (m, 9H), 6.74 (d, J=7.0 Hz, 1H), 4.85 (dd, J=25.8, 16.8Hz, 2H), 4.65 (s, 1H), 4.12 (s, 1H), 3.66-3.32 (m, 2H), 3.13 (dd,J=13.9, 6.2 Hz, 1H), 2.99 (q, J=10.6 Hz, 2H), 2.34 (s, 3H), 2.24 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 162.9, 155.2, 137.7, 136.1, 134.4,132.1, 131.4, 129.6, 129.1, 128.8, 126.5, 125.6, 122.8, 121.1, 120.7,106.7, 55.6, 44.8, 42.8, 41.6 (q, J=28.3, 26.1 Hz), 34.0, 21.1, 21.0.

(S)-2-fluoro-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction of tert-butyl(S)-(1-(1-(2-fluoroacetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (84%). [□]_(D)²⁰−64.341 (c 1.125, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J=7.8 Hz,2H), 7.06-6.92 (m, 6H), 6.89 (d, J=7.5 Hz, 3H), 6.72 (d, J=7.1 Hz, 1H),4.86 (d, J=2.9 Hz, 2H), 4.72 (d, J=47.4 Hz, 2H), 4.47 (s, 1H), 4.15 (s,1H), 3.69 (d, J=7.6 Hz, 1H), 3.58-3.38 (m, 1H), 3.14 (dd, J=13.9, 6.1Hz, 1H), 2.33 (s, 3H), 2.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 168.2,168.0, 155.0, 137.5, 136.1, 134.4, 132.3, 131.5, 129.6, 129.1, 128.8,126.5, 120.9, 120.5, 106.7, 80.2 (d, J=186.3 Hz), 55.4, 44.7, 41.4,34.5, 21.1, 21.1.

(S)-3-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-1,1-dimethylurea.Reaction of tert-butyl(S)-(1-(1-(3,3-dimethylureido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (60%). [□]_(D)²⁰−88.897 (c 1.008, CHCl₃). H NMR (400 MHz, CDCl₃, 50° C.) δ 7.10 (d,J=7.8 Hz, 2H), 7.01 (d, J=7.9 Hz, 4H), 6.97-6.81 (m, 5H), 6.70 (d, J=7.4Hz, 1H), 4.87 (dd, J=23.6, 16.8 Hz, 2H), 4.78 (s, 1H), 3.97 (dd, J=13.8,8.1 Hz, 1H), 3.69 (d, J=15.1 Hz, 1H), 3.50 (dd, J=14.2, 9.2 Hz, 1H),3.14 (dd, J=14.0, 6.0 Hz, 1H), 2.78 (s, 6H), 2.32 (s, 3H), 2.23 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 158.7, 155.2, 137.4, 135.8, 132.4, 131.4,129.5, 129.0, 128.8, 126.5, 120.9, 120.4, 106.7, 56.4, 44.7, 43.6, 36.1,28.6, 21.1, 21.0.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)furan-2-carboxamide.Reaction of tert-butyl(S)-(1-(1-(furan-2-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (72%). [□]_(D)²⁰−68.255 (c 0.9175, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H),7.24-6.77 (m, 12H), 6.71 (d, J=7.4 Hz, 1H), 6.43 (dd, J=3.4, 1.7 Hz,1H), 4.87 (s, 2H), 4.70-4.20 (br, 1H), 4.26 (s, 1H), 3.80 (s, 1H), 3.51(t, J=11.9 Hz, 1H), 3.19 (dd, J=14.0, 6.0 Hz, 1H), 2.32 (s, 3H), 2.24(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.8, 155.1, 148.1, 144.0, 137.4,136.0, 134.5, 132.3, 131.4, 129.6, 129.1, 128.9, 126.4, 121.0, 120.6,113.8, 111.7, 106.7, 55.8, 44.7, 41.8, 34.6, 21.1, 21.1.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-6-methylpicolinamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(6-methylpicolinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (81%). [□]_(D)²⁰−25.524 (c 1.23, CHCl₃). H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 7.94(d, J=7.7 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H),7.12-6.74 (m, 10H), 6.66 (d, J=7.5 Hz, 1H), 4.87 (s, 2H), 4.51-3.88 (m,3H), 3.71-3.37 (m, 1H), 3.22 (dd, J=14.0, 6.0 Hz, 1H), 2.44 (s, 3H),2.29 (s, 3H), 2.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.1, 157.1,154.9, 148.9, 137.3, 137.1, 135.9, 134.5, 132.6, 131.6, 129.4, 129.1,128.9, 126.5, 125.7, 120.6, 120.3, 119.2, 106.6, 55.5, 44.6, 41.2, 35.1,24.2, 21.1, 21.1.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-3-methylpicolinamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(3-methylpicolinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (73%). [□]_(D)²⁰−17.973 (c 1.178, CHCl₃). H NMR (400 MHz, CDCl₃) δ 9.21-8.36 (br, 1H),8.27 (dd, J=4.6, 1.6 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.24 (dd, J=7.8,4.6 Hz, 1H), 7.19-6.74 (m, 10H), 6.65 (d, J=7.6 Hz, 1H), 4.86 (s, 2H),4.52-3.81 (m, 3H), 3.64-3.40 (br, 1H), 3.20 (dd, J=13.9, 5.7 Hz, 1H),2.69 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ166.6, 155.0, 147.2, 145.5, 140.6, 137.1, 135.8, 135.2, 134.5, 132.8,131.6, 129.4, 129.1, 128.9, 126.5, 125.4, 120.5, 120.2, 106.5, 55.5,44.6, 40.9, 35.1, 21.1, 21.1, 20.4.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)pyridazine-3-carboxamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(pyridazine-3-carboxamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (82%). [□]_(D)²⁰−31.599 (c 0.848, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 9.22 (dd, J=5.1,1.8 Hz, 1H), 8.24 (dd, J=8.5, 1.7 Hz, 1H), 7.59 (dd, J=8.4, 5.0 Hz, 1H),7.06 (dd, J=15.8, 7.7 Hz, 4H), 6.96 (d, J=7.8 Hz, 4H), 6.83 (d, J=7.9Hz, 3H), 6.65 (d, J=7.3 Hz, 1H), 4.86 (dd, J=20.7, 17.1 Hz, 2H),4.54-3.90 (m, 3H), 3.53 (s, 1H), 3.20 (dd, J=13.9, 6.0 Hz, 1H), 2.31 (s,3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 154.8, 152.6,152.5, 137.2, 135.9, 134.4, 132.6, 131.6, 129.5, 129.1, 128.9, 127.4,126.5, 125.6, 120.5, 120.3, 106.6, 55.4, 44.6, 41.4, 34.9, 21.1, 21.1.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)isoxazole-5-carboxamide.Reaction of tert-butyl(S)-(1-(1-(isoxazole-5-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (70%). [□]_(D)²⁰−53.504 (c 1.11, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.09(d, J=7.1 Hz, 2H), 7.04-6.87 (m, 8H), 6.85 (d, J=1.8 Hz, 1H), 6.74 (d,J=7.4 Hz, 1H), 6.72-6.49 (m, 1H), 4.90 (q, J=17.0 Hz, 3H), 4.36 (s, 1H),3.70 (d, J=13.2 Hz, 1H), 3.51 (dd, J=13.9, 9.4 Hz, 1H), 3.22 (dd,J=14.1, 6.3 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 163.5, 156.2, 154.8, 150.7, 137.6, 136.1, 131.9, 131.3, 129.6,129.1, 128.8, 126.4, 126.1, 121.2, 120.9, 107.0, 105.9, 55.9, 44.9,42.4, 34.2, 21.1, 21.0.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-5-methylisoxazole-4-carboxamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(5-methylisoxazole-4-carboxamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (78%). [□]_(D)²⁰−53.640 (c 1.178, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H),7.16-6.50 (m, 12H), 5.17 (s, 1H), 4.86 (q, J=17.0 Hz, 2H), 4.27 (s, 1H),3.59 (s, 2H), 3.21 (s, 1H), 2.66 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 172.1, 161.4, 155.1, 148.8, 137.8, 136.1,134.4, 131.8, 131.2, 129.7, 129.1, 128.8, 126.3, 121.5, 112.1, 107.1,56.3, 44.9, 42.7, 34.1, 21.1, 21.0, 12.3.

(S)-1,1-difluoro-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)methanesulfonamide.Reaction of tert-butyl(S)-(1-(1-((difluoromethyl)sulfonamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (91%). [□]_(D)²⁰−61.878 (c 0.740, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.18-6.60 (m,13H), 6.04 (t, J=54.7 Hz, 1H), 5.10 (q, J=16.8 Hz, 2H), 4.61 (s, 1H),3.87 (dd, J=13.5, 5.3 Hz, 1H), 3.70 (d, J=13.5 Hz, 1H), 3.48 (dd,J=14.2, 10.1 Hz, 1H), 3.13 (dd, J=14.1, 5.4 Hz, 1H), 2.29 (s, 3H), 2.17(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 153.2, 137.9, 136.1, 134.0, 131.2,130.5, 129.6, 129.0, 128.8, 126.7, 126.6, 122.3, 122.0, 114.7 (t,J=278.5 Hz), 108.4, 59.3, 47.8, 45.5, 33.8, 21.1, 21.0.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-1,4-dimethyl-1H-imidazole-5-carboxamide.Reaction of tert-butyl(S)-(1-(1-(1,4-dimethyl-1H-imidazole-5-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (67%). [□]_(D)²⁰−80.382 (c 1.01, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=7.7 Hz,2H), 7.05-6.93 (m, 6H), 6.88 (s, 3H), 6.71 (d, J=7.0 Hz, 1H), 5.19-4.60(m, 3H), 4.24 (s, 1H), 3.78 (d, J=12.9 Hz, 1H), 3.72 (s, 3H), 3.50 (t,J=11.0 Hz, 1H), 3.19 (dd, J=13.8, 6.3 Hz, 1H), 2.32 (s, 3H), 2.24 (s,6H). ¹³C NMR (100 MHz, CDCl₃) δ 161.6, 154.9, 140.5, 139.1, 137.6,136.0, 134.5, 132.3, 131.5, 129.6, 129.1, 128.9, 126.5, 120.8, 120.5,106.6, 55.4, 44.7, 41.9, 34.8, 34.0, 21.1, 21.0, 15.1.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(1H-pyrrol-1-yl)acetamide.Reaction of tert-butyl(S)-(1-(1-(2-(1H-pyrrol-1-yl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (53%). [□]_(D)²⁰−49.450 (c 0.833, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J=7.8 Hz,2H), 6.99 (dt, J=13.8, 7.9 Hz, 8H), 6.71 (d, 2H), 6.32 (s, 2H), 6.05 (s,2H), 4.89-4.74 (m, 2H), 4.65 (s, 1H), 4.52-4.32 (m, 2H), 3.95 (s, 1H),3.66 (d, J=13.7 Hz, 1H), 3.42 (t, J=8.9, 5.7 Hz, 1H), 3.07 (dd, J=13.9,6.3 Hz, 1H), 2.35 (s, 3H), 2.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ169.25, 154.47, 137.52, 135.99, 134.45, 132.46, 131.54, 129.56, 129.10,128.79, 126.61, 121.60, 120.73, 120.37, 109.53, 106.54, 55.06, 52.95,44.72, 41.32, 28.56, 21.14, 21.04.

(S)—N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)nicotinamide.Reaction of tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(nicotinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure H) yielded the title product as a yellow gel (51%). [□]_(D)²⁰−75.435 (c 1.134, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 9.12 (s, 1H), 8.65(d, J=5.3 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 7.07 (s, 3H),7.02-6.89 (m, 8H), 6.77 (d, J=7.5 Hz, 1H), 4.90 (q, J=15.3 Hz, 2H), 4.39(dd, J=14.4, 6.9 Hz, 2H), 3.63 (d, J=42.4 Hz, 2H), 3.22 (dd, J=13.8, 6.1Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.57,154.98, 151.78, 148.73, 137.73, 136.10, 135.24, 134.41, 131.73, 131.23,130.08, 129.65, 129.14, 128.78, 126.34, 123.25, 121.22, 106.94, 56.29,44.90, 43.37, 34.02, 21.11, 21.03.

Synthesis with General Procedure (I).

tert-butyl-1-(1-(2-(4-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate

Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetic acid (Procedure I)yielded the title product as a yellow foam (90%). ¹H NMR (400 MHz,CDCl₃, 50° C.) δ 7.15-6.98 (m, 8H), 6.94 (d, J=5.0 Hz, 3H), 6.87 (s,4H), 6.31 (s, 1H), 5.15 (dd, J=37.4, 16.1 Hz, 2H), 4.84 (s, 1H), 4.26(s, 1H), 3.59 (s, 1H), 3.26 (s, 3H), 3.07 (dd, J=14.0, 6.3 Hz, 1H), 2.30(s, 3H), 2.24 (s, 3H), 1.53 (s, 9H), 1.49 (s, 9H).

tert-butyl-1-(1-(2-(3-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(3-((tert-butoxycarbonyl)amino)phenyl)acetic acid (Procedure I)yielded the title product as a yellow foam (84%). ¹H NMR (400 MHz,CDCl₃, 50° C.) δ 7.41 (d, J=7.9 Hz, 1H), 7.16-7.02 (m, 4H), 7.02-6.86(m, 8H), 6.70 (dd, J=2.4, 1.3 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 6.47 (s,1H), 5.13 (q, J=15.8 Hz, 2H), 4.87 (s, 1H), 4.23 (s, 1H), 3.76-3.49 (m,1H), 3.29 (s, 3H), 3.08 (dd, J=14.0, 6.3 Hz, 1H), 2.29 (s, 3H), 2.24 (s,3H), 1.51 (s, 9H), 1.49 (s, 9H).

tert-butyl-1-(1-(2-(2-((tert-butoxycarbonyl)amino)phenyl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(2-((tert-butoxycarbonyl)amino)phenyl)acetic acid (Procedure I)yielded the title product as a yellow foam (85%). ¹H NMR (400 MHz,CDCl₃, 50° C.) δ 8.79 (s, 1H), 8.66 (s, 1H), 7.69 (d, J=8.2 Hz, 1H),7.14-6.99 (m, 6H), 6.99-6.89 (m, 4H), 6.85 (d, J=7.7 Hz, 2H), 6.75 (t,J=7.5 Hz, 1H), 5.20 (d, J=15.6 Hz, 1H), 5.08 (d, J=15.9 Hz, 1H), 4.82(s, 1H), 4.31 (s, 1H), 3.49 (s, 1H), 3.34 (s, 2H), 3.24 (s, 1H), 3.08(dd, J=13.9, 6.7 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.54 (s, 9H), 1.51(s, 9H).

tert-butyl-(1-(1-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith (tert-butoxycarbonyl)glycine (Procedure I) yielded the titleproduct as a yellow foam (95%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 7.78(s, 1H), 7.39 (s, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.08 (d, J=8.1 Hz, 3H),7.04-6.91 (m, 7H), 5.45-5.06 (m, 3H), 4.91 (s, 1H), 4.43-4.16 (m, 1H),3.78-3.52 (m, 3H), 3.43-3.24 (m, 1H), 3.16 (dd, J=14.0, 7.0 Hz, 1H),2.30 (s, 3H), 2.26 (s, 3H), 1.51 (s, 9H), 1.39 (s, 9H).

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(methylamino)acetamide.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewithtert-butyl-(2-((2-(2-((tert-butoxycarbonyl)imino)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)amino)-2-oxoethyl)(methyl)carbamate(Procedure I) yielded the title product as a yellow gel (>95%). ¹H NMR(400 MHz, CD₃OD, 50° C.) δ 7.39-6.81 (m, 11H), 6.77-6.70 (m, 1H), 4.89(dt, J=34.9, 17.2 Hz, 3H), 3.92 (q, J=18.4, 15.6 Hz, 1H), 3.85-3.74 (m,1H), 3.40 (d, J=13.3 Hz, 1H), 3.09 (dd, J=14.1, 5.2 Hz, 1H), 3.03 (s,2H), 2.27 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H). ¹³C NMR (100 MHz, CD₃OD)δ 172.7, 136.7, 135.6, 134.3, 133.1, 128.8, 128.6, 126.4, 120.4, 118.3,115.4, 109.3, 107.2, 55.3, 53.0, 52.9, 43.8, 40.3, 40.0, 34.6, 19.8,19.7.

tert-butyl-(1-(4-methylbenzyl)-3-(1-(2-(pyrimidin-2-yl)acetamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(pyrimidin-2-yl)acetic acid (Procedure I) yielded the titleproduct as a yellow foam (83%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ8.57-7.94 (m, 2H), 7.04 (s, 6H), 6.94 (s, 6H), 5.18 (s, 2H), 4.91 (s,1H), 4.24 (s, 1H), 3.94-3.63 (m, 3H), 3.36 (s, 1H), 3.13 (dd, J=14.0,6.3 Hz, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 1.49 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-(3,3,3-trifluoropropanamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 3,3,3-trifluoropropanoic acid (Procedure I) yielded the titleproduct as a yellow foam (73%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 8.65(s, 1H), 7.23-7.05 (m, 4H), 7.04-6.92 (m, 5H), 6.90 (d, J=7.7 Hz, 2H),5.18 (s, 2H), 4.86 (s, 1H), 4.37 (s, 1H), 3.57 (d, J=14.0 Hz, 1H),3.39-3.24 (m, 1H), 3.14 (dd, J=14.0, 6.6 Hz, 1H), 2.99-2.76 (m, 2H),2.31 (s, 3H), 2.26 (s, 3H), 1.50 (s, 9H).

tert-butyl(S)-(1-(1-(2-fluoroacetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-fluoroacetic acid (Procedure I) yielded the title product as ayellow foam (80%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 7.13 (t, J=7.7 Hz,1H), 7.07 (d, J=8.0 Hz, 3H), 6.97 (dt, J=14.8, 7.7 Hz, 8H), 5.18 (d,J=3.3 Hz, 2H), 4.97 (s, 1H), 4.59 (d, J=47.3 Hz, 2H), 4.43-4.23 (m, 1H),3.74 (d, J=14.0 Hz, 1H), 3.35 (t, J=11.2 Hz, 1H), 3.15 (dd, J=14.0, 6.5Hz, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.51 (s, 9H).

tert-butyl(S)-(1-(1-(furan-2-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith furan-2-carboxylic acid (Procedure I) yielded the title product asa yellow gel (67%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 8.60-7.95 (br,1H), 7.37 (s, 1H), 7.19-6.79 (m, 12H), 6.37 (dd, J=3.6, 1.7 Hz, 1H),5.17 (s, 2H), 5.02 (s, 1H), 4.47 (s, 1H), 3.84 (d, J=13.3 Hz, 1H),3.46-3.29 (m, 1H), 3.19 (dd, J=14.0, 6.5 Hz, 1H), 2.28 (s, 3H), 2.26 (s,3H), 1.52 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(6-methylpicolinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith from 6-methylpicolinic acid (Procedure I) yielded the title productas a yellow foam (78%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 8.57 (s, 1H),7.90 (d, J=7.7 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H),7.14-6.69 (m, 11H), 5.18 (s, 2H), 5.12 (s, 1H), 4.51-4.05 (m, 2H), 3.49(s, 1H), 3.24 (dd, J=13.9, 5.9 Hz, 1H), 2.48 (s, 3H), 2.27 (s, 3H), 2.22(s, 3H), 1.53 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(3-methylpicolinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 3-methylpicolinic acid (Procedure I) yielded the title product as ayellow foam (85%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 8.50 (s, 1H),8.35-8.17 (m, 1H), 7.48 (d, J=7.7 Hz, 1H), 7.21 (dd, J=7.8, 4.6 Hz, 1H),7.12-6.89 (m, 10H), 6.86 (d, J=7.9 Hz, 1H), 5.16 (dd, J=23.1, 16.3 Hz,2H), 5.10 (s, 1H), 4.33-4.08 (m, 2H), 3.51 (s, 1H), 3.23 (dd, J=14.1,6.1 Hz, 1H), 2.61 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H), 1.50 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(pyridazine-3-carboxamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith pyridazine-3-carboxylic acid (Procedure I) yielded the titleproduct as a yellow foam (56%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 9.21(dd, J=5.0, 1.8 Hz, 1H), 8.69 (s, 1H), 8.18 (dd, J=8.4, 1.8 Hz, 1H),7.55 (dd, J=8.4, 5.0 Hz, 1H), 7.11-6.91 (m, 10H), 6.87 (d, J=7.8 Hz,1H), 5.18 (q, J=15.9 Hz, 3H), 4.33 (s, 1H), 4.27-4.13 (m, 1H), 3.51 (s,1H), 3.25 (dd, J=14.0, 6.5 Hz, 1H), 2.29 (s, 3H), 2.23 (s, 3H), 1.51 (s,9H).

tert-butyl(S)-(1-(1-(isoxazole-5-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith isoxazole-5-carboxylic acid (Procedure I) yielded the title productas a yellow gel (85%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 9.07 (s, 1H),8.19 (d, J=1.7 Hz, 1H), 7.39 (s, 1H), 7.22-6.87 (m, 11H), 6.81 (d, J=1.8Hz, 1H), 5.17 (s, 2H), 5.02 (s, 1H), 4.54 (s, 1H), 3.78 (d, J=14.3 Hz,1H), 3.38 (t, J=12.1 Hz, 1H), 3.20 (dd, J=14.0, 6.7 Hz, 1H), 2.29 (s,3H), 2.27 (s, 3H), 1.53 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(5-methylisoxazole-4-carboxamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 5-methylisoxazole-4-carboxylic acid (Procedure I) yielded the titleproduct as a yellow foam (79%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 8.90(s, 1H), 8.60 (s, 1H), 7.47 (s, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.13 (t,J=7.7 Hz, 1H), 7.06-6.90 (m, 9H), 5.25 (d, J=15.6 Hz, 1H), 5.10 (d,J=15.6 Hz, 1H), 4.97 (s, 1H), 4.52 (s, 1H), 3.62 (s, 1H), 3.31 (s, 1H),3.20 (dd, J=13.9, 7.1 Hz, 1H), 2.56 (s, 3H), 2.28 (s, 6H), 1.52 (s, 9H).

tert-butyl(S)-(1-(1-(1,4-dimethyl-1H-imidazole-5-carboxamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 1,4-dimethyl-1H-imidazole-5-carboxylic acid (Procedure I) yieldedthe title product as a white foam (80%). ¹H NMR (400 MHz, CDCl₃, 50° C.)δ 7.35 (s, 1H), 7.17 (s, 1H), 7.15-6.66 (m, 11H), 5.33-4.94 (m, 3H),4.50 (s, 1H), 3.77 (s, 1H), 3.47 (s, 3H), 3.36 (s, 1H), 3.17 (dd,J=13.9, 6.6 Hz, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 2.07 (s, 3H), 1.49 (s,9H).

tert-butyl(S)-(1-(1-(2-(1H-pyrrol-1-yl)acetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-(1H-pyrrol-1-yl)acetic acid (Procedure I) yielded the titleproduct as a yellow gel (76%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ7.18-7.06 (m, 4H), 7.03 (d, J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 6H), 6.32(s, 2H), 5.98 (s, 2H), 5.18 (q, J=15.6 Hz, 2H), 4.89 (s, 1H), 4.33 (s,2H), 4.14 (s, 1H), 3.68 (s, 1H), 3.36 (s, 1H), 3.11 (dd, J=14.0, 6.6 Hz,1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.49 (s, 9H).

tert-butyl(S)-(1-(4-methylbenzyl)-3-(1-(nicotinamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction of tert-butyl(S)-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith nicotinic acid (Procedure I) yielded the title product as a yellowgel (53%). ¹H NMR (400 MHz, CDCl₃, 50° C.) δ 9.07 (s, 1H), 8.63 (dd,J=4.8, 1.7 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.24-7.15 (m,2H), 7.10 (t, J=7.7 Hz, 1H), 7.05-6.88 (m, 9H), 5.17 (dd, J=27.8, 15.2Hz, 2H), 5.06 (s, 1H), 4.63 (s, 1H), 3.74 (d, J=12.5 Hz, 1H), 3.34 (s,1H), 3.22 (dd, J=13.9, 6.9 Hz, 1H), 2.28 (s, 3H), 2.27 (s, 3H), 1.52 (s,9H).

Synthesis with General Procedure (J).

tert-butyl(1-(1-(ethylsulfonamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate

Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith ethanesulfonyl chloride (Procedure J) yielded the title product(71%) as a white solid (46%). ¹H NMR (400 MHz, CDCl₃) δ 7.37 (br s, 1H),7.18 (m, 1H), 7.12 (m, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.00 (m, 5H), 6.91(d, J=7.8 Hz, 2H), 5.20 (d, J=15.7 Hz, 1H), 5.15 (d, J=15.8 Hz, 1H),4.84 (br s, 1H), 4.04 (m, 1H), 3.55 (ddd, J=13.2, 4.8, 3.2 Hz, 1H),3.33-3.26 (m, 1H), 3.14 (dd, J=14.0, 6.6 Hz, 1H), 2.78 (br m, 2H), 2.30(s, 3H), 2.27 (s, 3H), 1.49 (s, 9H), 1.16-1.01 (br t, J=7.2 Hz, 3H). MS(APCI) calcd for: C₃₂H₄₁N₄O₄S (MH⁺): 577.3, found 577.1.

tert-butyl(1-(1-(cyclopropanesulfonamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith cyclopropanesulfonyl chloride (Procedure J) yielded the titleproduct (46%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (br s,1H), 7.22-7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.08 (d, J=7.5 Hz, 2H),7.04-6.96 (m, 5H), 6.92 (d, J=7.7 Hz, 2H), 6.78 (br s, 1H), 5.20 (d,J=15.7 Hz, 1H), 5.15 (d, J=15.9 Hz, 1H), 4.87 (br s, 1H), 4.10-3.99 (m,1H), 3.63 (dt, J=13.1, 4.1 Hz, 1H), 3.31 (dd, J=13.5, 9.5 Hz, 1H), 3.15(dd, J=14.0, 6.8 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 2.20-2.10 (m, 1H),1.49 (s, 9H), 1.05-0.94 (m, 2H), 0.76-0.58 (m, 2H). MS (APCI) calcd for:C₃₃H₄₁N₄O₄S (MH⁺): 589.3, found 589.3.

tert-butyl(1-(4-methylbenzyl)-3-(1-(phenylsulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith benzenesulfonyl chloride (Procedure J) yielded the title product(62%) as a yellow foam. ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.58 (m, 3H),7.21-7.02 (m, 7H), 7.02-6.97 (m, 2H), 6.97-6.87 (m, 4H), 6.79 (br s,2H), 5.15 (d, J=16.1 Hz, 1H), 5.08 (d, J=16.0 Hz, 1H), 4.75 (br s, 1H),3.90 (td, J=12.1, 7.0 Hz, 1H), 3.39 (ddd, J=13.0, 4.4, 2.4 Hz, 1H),3.26-3.10 (m, 1H), 3.03 (dd, J=14.0, 6.5 Hz, 1H), 2.31 (s, 3H), 2.25 (s,3H), 1.48 (s, 9H). MS (APCI) calcd for: C₃₆H₄₁N₄O₄S (MH⁺): 625.3, found625.2.

tert-butyl(1-(4-methylbenzyl)-3-(1-(methylsulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith methanesulfonyl chloride (Procedure J) yielded the title product(34%). ¹H NMR (400 MHz, CDCl₃) δ 7.36 (br s, 1H), 7.20 (br t, J=7.5 Hz,1H), 7.12 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.9 Hz, 2H), 7.00 (m, 5H), 6.91(d, J=7.7 Hz, 2H), 6.82 (br s, 1H), 5.20 (d, J=15.7 Hz, 1H), 5.14 (d,J=15.8 Hz, 1H), 4.85 (br s, 1H), 4.06 (ddd, J=12.9, 10.7, 7.0 Hz, 1H),3.57 (ddd, J=13.2, 4.7, 3.1 Hz, 1H), 3.30 (dd, J=13.9, 8.9 Hz, 1H), 3.15(dd, J=13.9, 6.7 Hz, 1H), 2.66 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H), 1.49(s, 9H). MS (APCI) calcd for: C₃₁H₃₉N₄O₄S (MH⁺): 563.3, found 563.3.

tert-butyl(1-(4-methylbenzyl)-3-(1-((1-methylethyl)sulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith 2-propanesulfonyl chloride (Procedure J) yielded the title product(29%). H NMR (400 MHz, CDCl₃) δ 7.33 (br s, 1H), 7.16 (br t, J=8.3 Hz,1H), 7.14-7.09 (m, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.05-6.95 (m, 5H), 6.91(d, J=7.7 Hz, 2H), 6.85-6.44 (br m, 1H), 5.22 (d, J=16.0 Hz, 1H), 5.17(d, J=15.6 Hz, 1H), 4.84 (br s, 1H), 4.06 (ddd, J=13.1, 10.6, 7.1 Hz,1H), 3.58 (ddd, J=13.3, 5.0, 3.5 Hz, 1H), 3.41-3.22 (m, 1H), 3.13 (dd,J=14.0, 6.5 Hz, 1H), 3.04-2.85 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.49(s, 9H), 1.22 (d, J=6.8 Hz, 3H), 1.13 (br s, 3H). MS (APCI) calcd for:C₃₃H₄₃N₄O₄S (MH⁺): 591.3, found 591.2.

tert-butyl(1-(4-methylbenzyl)-3-(1-((phenylmethyl)sulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith phenylmethanesulfonyl chloride (Procedure J) yielded the titleproduct (64%). ¹H NMR (400 MHz, CDCl₃) δ 7.81-7.60 (m, 1H), 7.43-7.22(m, 4H), 7.22-7.09 (m, 2H), 7.09-7.04 (m, 3H), 7.03-6.90 (m, 6H), 6.85(d, J=7.7 Hz, 2H), 5.20 (d, J=15.7 Hz, 1H), 5.12 (d, J=15.8 Hz, 1H),4.74 (br s, 1H), 4.11 (d, J=13.5 Hz, 1H), 4.05 (d, J=13.9 Hz, 1H), 3.86(ddd, J=13.2, 10.4, 6.4 Hz, 1H), 3.31-3.13 (m, 2H), 3.02 (dd, J=14.0,6.5 Hz, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 1.49 (s, 9H). MS (APCI) calcdfor: C₃₇H₄₃N₄O₄S (MH⁺): 639.3, found 639.2.

tert-butyl(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-((trifluoromethyl)sulfonamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate.Reaction oftert-butyl-(1-(1-amino-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamatewith trifluoromethanesulfonyl chloride (Procedure J) yielded the titleproduct (29%). H NMR (400 MHz, CDCl₃) δ 7.73-7.30 (br s, 1H), 7.24-7.11(m, 2H), 7.09 (d, J=7.7 Hz, 2H), 7.05-6.90 (m, 5H), 6.85 (d, J=7.6 Hz,2H), 5.23 (d, J=15.1 Hz, 1H), 5.17 (d, J=15.8 Hz, 1H), 4.85 (br s, 1H),4.16 (dd, J=12.2, 11.9 Hz, 1H), 3.69 (dd, J=12.7, 4.0 Hz, 1H), 3.43-3.23(m, 1H), 3.13 (dd, J=14.0, 6.2 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 1.48(s, 9H). MS (APCI) calcd for: C₃₁H₃₆F₃N₄O₄S (MH⁺): 617.2, found 617.2.

Synthesis with General Procedure (K).

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)ethanesulfonamide

Reaction of tert-butyl(1-(1-(ethylsulfonamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product as an off-white solid (94%). ¹HNMR (400 MHz, CDCl₃) δ 7.12 (d, J=7.8 Hz, 2H), 7.07-6.98 (m, 4H), 6.95(d, J=7.8 Hz, 2H), 6.93-6.86 (m, 2H), 6.81 (br s, 1H), 6.76-6.66 (m,1H), 4.88 (d, J=16.9 Hz, 1H), 4.82 (d, J=16.7 Hz, 1H), 4.65 (br s, 1H),3.82 (dd, J=13.0, 7.4 Hz, 1H), 3.56-3.42 (m, 2H), 3.23 (dd, J=13.9, 6.5Hz, 1H), 2.92 (q, J=7.4 Hz, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 1.24 (t,J=7.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.0, 137.8, 136.2, 134.5,132.3, 131.6, 129.8, 129.2, 129.1, 126.7, 121.1, 120.8, 110.1, 107.5,106.9, 56.5, 46.7, 45.7, 45.0, 34.3, 21.3, 21.2, 8.4.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)cyclopropanesulfonamide.Reaction of tert-butyl(1-(1-(cyclopropanesulfonamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product as an off-white solid (97%). ¹HNMR (400 MHz, CDCl₃) δ 7.13 (d, J=7.9 Hz, 2H), 7.08-7.00 (m, 4H), 6.97(d, J=7.8 Hz, 2H), 6.94-6.87 (m, 2H), 6.83 (br s, 1H), 6.77-6.68 (m,1H), 4.88 (d, J=16.8 Hz, 1H), 4.82 (d, J=16.7 Hz, 1H), 4.67 (br s, 1H),3.83 (dd, J=13.0, 7.5 Hz, 1H), 3.58 (dd, J=13.0, 3.2 Hz, 1H), 3.43 (dd,J=13.9, 8.6 Hz, 1H), 3.25 (dd, J=13.9, 6.7 Hz, 1H), 2.33 (s, 3H),2.32-2.27 (m, 1H), 2.24 (s, 3H), 1.13-0.99 (m, 2H), 0.86-0.72 (m, 2H).¹³C NMR (100 MHz, CDCl₃) δ 155.1, 137.8, 136.2, 134.5, 132.3, 131.7,129.8, 129.3, 129.1, 126.7, 121.1, 120.8, 107.3, 106.9, 56.5, 45.6,45.0, 34.4, 30.0, 21.3, 21.2, 5.3, 5.1.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)benzenesulfonamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-(phenylsulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product as a yellow solid (61%). ¹H NMR(400 MHz, CDCl₃) δ 7.77 (d, J=7.3 Hz, 2H), 7.49-7.41 (m, 1H), 7.40-7.33(m 2H), 7.13 (d, J=7.8 Hz, 2H), 7.01 (d, J=7.8 Hz, 2H), 6.98 (d, J=8.1Hz, 2H), 6.94 (d, J=8.0 Hz, 2H), 6.90-6.83 (m, 2H), 6.75-6.60 (m, 2H),4.85 (d, J=16.8 Hz, 1H), 4.79 (d, J=16.8 Hz, 1H), 4.51 (br s, 1H), 3.65(dd, J=12.8, 6.9 Hz, 1H), 3.35 (dd, J=13.8, 8.5 Hz, 1H), 3.25 (d,J=13.0, 2.8 Hz, 1H), 3.19 (dd, J=13.9, 6.9 Hz, 1H), 2.35 (s, 3H), 2.23(s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.0, 140.4, 137.8, 136.2, 134.5,132.2, 132.1, 131.5, 129.8, 129.2, 129.1, 128.9, 127.0, 126.7, 121.1,120.8, 106.9, 56.3, 45.8, 45.0, 34.3, 21.3, 21.2

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)methanesulfonamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-(methylsulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (89%). ¹H NMR (400 MHz, CDCl₃) δ7.13 (d, J=7.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 7.01 (d, J=7.6 Hz, 2H),6.97 (d, J=7.9 Hz, 2H), 6.94-6.87 (m, 2H), 6.87-6.78 (br m, 1H),6.77-6.72 (m, 1H), 4.87 (d, J=16.8 Hz, 1H), 4.81 (d, J=16.8 Hz, 1H),4.65 (br s, 1H), 3.81 (dd, J=13.0, 7.4 Hz, 1H), 3.51 (dd, J=13.0, 3.1Hz, 1H), 3.43 (dd, J=13.9, 8.7 Hz, 1H), 3.24 (dd, J=13.9, 6.7 Hz, 1H),2.82 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ155.1, 137.9, 136.3, 134.4, 132.2, 131.6, 129.8, 129.3, 129.1, 126.7,121.2, 120.9, 107.4, 107.0, 56.4, 45.7, 45.0, 40.1, 34.3, 21.3, 21.2.

Methyl(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamate.Reaction of tert-butyl(1-(1-((methoxycarbonyl)amino)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (81%). ¹H NMR (400 MHz, CDCl₃) δ7.10 (d, J=7.8 Hz, 2H), 6.98 (m, 5H), 6.88 (m, 3H), 6.69 (d, J=7.3 Hz,1H), 4.89 (d, J=16.9 Hz, 1H), 4.83 (d, J=16.7 Hz, 1H), 4.75 (br s, 1H),3.93 (br s, 1H), 3.75-3.63 (m, 1H), 3.61 (s, 3H), 3.52-3.32 (m, 1H),3.12 (dd, J=13.9, 6.0 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H). ¹³C NMR (101MHz, CDCl₃) δ 157.4, 155.1, 137.5, 136.1, 132.6, 131.7, 129.7, 129.2,129.0, 126.7, 120.9, 120.5, 111.6, 106.8, 56.2, 52.2, 44.9, 43.2, 29.9,21.3, 21.2.

Ethyl(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamate.Reaction of tert-butyl(1-(1-((ethoxycarbonyl)amino)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (92%). ¹H NMR (400 MHz, CDCl₃) δ7.10 (d, J=7.8 Hz, 2H), 7.05-6.93 (m, 6H), 6.93-6.81 (m, 2H), 6.70 (d,J=7.4 Hz, 1H), 4.92 (d, J=17.0 Hz, 1H), 4.84 (d, J=16.7 Hz, 1H), 4.78(br s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.92 (br s, 1H), 3.78-3.60 (m, 1H),3.43 (br s, 1H), 3.12 (dd, J=13.9, 5.9 Hz, 1H), 2.32 (s, 3H), 2.24 (s,3H), 1.17 (t, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 156.7, 154.1,138.7, 137.2, 135.7, 132.3, 131.3, 129.3, 128.9, 128.7, 126.4, 120.6,120.2, 106.6, 60.6, 55.8, 44.6, 42.7, 29.5, 20.94, 20.88, 14.5.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)propane-2-sulfonamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-((1-methylethyl)sulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (88%). ¹H NMR (400 MHz, CDCl₃) δ7.13 (d, J=7.9 Hz, 2H), 7.07-6.98 (m, 4H), 6.95 (d, J=7.8 Hz, 2H),6.92-6.83 (m, 2H), 6.77 (br s, 1H), 6.75-6.66 (m, 1H), 4.88 (d, J=16.8Hz, 1H), 4.82 (d, J=16.8 Hz, 1H), 4.60 (br s, 1H), 3.85 (dd, J=13.1, 7.3Hz, 1H), 3.52 (dd, J=13.0, 3.0 Hz, 1H), 3.48 (dd, J=13.6, 9.2 Hz, 1H),3.20 (dd, J=13.9, 6.4 Hz, 1H), 3.06 (qq, J=6.9, 6.8 Hz, 1H), 2.34 (s,3H), 2.23 (s, 3H), 1.30 (d, J=6.9 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 155.1, 137.8, 136.2, 134.6, 132.3, 131.6, 129.8,129.3, 129.2, 129.1, 126.7, 121.0, 120.7, 107.3, 106.8, 56.7, 53.1,46.1, 44.9, 34.3, 21.3, 21.2, 16.7, 16.7.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-1-phenylmethanesulfonamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-((phenylmethyl)sulfonamido)-3-(p-tolyl)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (95%). ¹H NMR (400 MHz, CDCl₃) δ7.36-7.29 (m, 2H), 7.30-7.19 (m, 5H), 7.13 (d, J=7.8 Hz, 2H), 7.01 (d,J=7.4 Hz, 2H), 6.97 (d, J=8.2 Hz, 2H), 6.93 (d, J=8.1 Hz, 2H), 6.91-6.85(m, 2H), 6.77-6.67 (m, 2H), 4.84 (d, J=16.8 Hz, 1H), 4.78 (d, J=16.8 Hz,1H), 4.49 (br s, 1H), 4.18 (s, 2H), 3.63 (dd, J=13.0, 7.1 Hz, 1H), 3.43(dd, J=13.9, 9.1 Hz, 1H), 3.26 (dd, J=13.0, 3.1 Hz, 1H), 3.11 (dd,J=13.9, 6.2 Hz, 1H), 2.33 (s, 3H), 2.23 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 154.9, 137.8, 136.1, 134.5, 132.3, 131.6, 130.8, 129.8, 129.8,129.2, 129.1, 128.7, 128.5, 126.7, 121.1, 120.7, 107.3, 106.8, 59.1,56.6, 46.4, 44.9, 34.2, 21.3, 21.2.

1,1,1-trifluoro-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)methanesulfonamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-((trifluoromethyl)sulfonamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (22%). ¹H NMR (400 MHz,d₆-acetone) δ 7.34 (br s, 1H), 7.33-7.27 (m, 1H), 7.23 (d, J=8.0 Hz,2H), 7.17 (d, J=8.0 Hz, 2H), 7.15-7.08 (m, 2H), 7.01 (d, J=8.0 Hz, 2H),6.82 (d, J=7.7 Hz, 2H), 5.46 (s, 2H), 5.15 (br s, 1H), 3.82 (br d,J=13.9 Hz, 1H), 3.68 (d, J=13.5 Hz, 1H), 3.59 (dd, J=11.1, 3.3 Hz, 1H),3.12 (dd, J=14.2, 4.9 Hz, 1H), 2.33 (s, 3H), 2.10 (s, 3H). ¹³C NMR (101MHz, d₆-acetone) δ 152.5, 138.8, 136.6, 135.1, 132.2, 130.7, 130.4,129.8, 129.6, 127.9, 124.22, 124.16, 124.0, 111.3, 110.8, 61.6, 49.9,46.5, 34.4, 21.1, 20.9.

1-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)urea.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-ureidopropan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (73%). ¹H NMR (400 MHz, CDCl₃) δ7.16-7.05 (m, 2H), 7.05-6.76 (m, 8H), 6.70 (d, J=7.4 Hz, 1H), 4.84 (d,J=16.8 Hz, 1H), 4.77 (d, J=16.7 Hz, 1H), 4.65 (br s, 1H), 4.37 (br s,1H), 3.98 (br s, 1H), 3.70-3.54 (m, 1H), 3.53-3.33 (m, 1H), 3.12 (dd,J=13.9, 6.0 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 159.2, 155.4, 137.4, 136.0, 134.5, 132.5, 131.4, 129.6, 129.4,129.24, 129.18, 128.9, 127.3, 126.5, 121.1, 120.7, 107.0, 56.7, 44.5,42.3, 34.8, 21.23, 21.19.

(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamicacid. Reaction of(2-(2-((tert-butoxycarbonyl)imino)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamicacid (Procedure K) yielded the title product (93%) as a mixture ofrotamers. ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.55 (m, 4H), 7.31 (d, J=7.7Hz, 0.5H), 7.22-6.88 (m, 8H), 6.82 (d, J=7.7 Hz, 1H), 6.73-6.34 (m, 2H),5.28 (br s, 0.6H), 4.97-4.58 (m, 3H), 4.47-4.22 (m, 0.7H), 4.14 (d,J=5.3 Hz, 0.5H), 4.11 (d, J=6.3 Hz, 0.4H), 3.90 (s, 0.4H), 3.81-3.47 (brm, 1H), 3.46-3.34 (m, 1H), 3.24 (dd, J=14.1, 6.1 Hz, 1H), 2.47-2.06 (m,6H). ¹³C NMR (101 MHz, CDCl₃) δ 168.3, 168.1, 155.0, 154.1, 137.4,136.9, 136.2, 135.9, 135.0, 134.0, 133.8, 133.0, 132.7, 131.9, 131.6,129.4, 129.6, 129.4, 129.3, 129.2, 128.8, 126.7, 123.5, 123.2, 120.7,120.4, 119.8, 109.0, 107.0, 106.2, 105.7, 55.1, 53.5, 44.9, 44.5, 39.0,38.9, 35.7, 34.6, 29.9, 21.24, 21.18.

N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)-2-(p-tolyl)acetamide.Reaction of tert-butyl(1-(4-methylbenzyl)-3-(1-(p-tolyl)-3-(2-(p-tolyl)acetamido)propan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (84%). ¹H NMR (400 MHz, CDCl₃) δ7.12 (d, J=7.7 Hz, 2H), 7.05-6.73 (m, 13H), 6.70 (dd, J=6.5, 1.8 Hz,1H), 4.82 (d, J=16.8 Hz, 1H), 4.77 (d, J=16.8 Hz, 1H), 4.67 (br s, 1H),3.93 (br s, 1H), 3.66 (br d, J=13.1 Hz, 1H), 3.44 (br s, 1H), 3.41 (s,2H), 3.06 (dd, J=13.8, 6.0 Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.24 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 171.8, 154.8, 137.6, 136.6, 136.0,134.7, 132.6, 131.9, 131.6, 129.7, 129.5, 129.4, 129.2, 128.9, 126.6,120.9, 120.4, 106.5, 55.4, 44.8, 43.5, 41.8, 34.7, 21.3, 21.22, 21.17.

2-hydroxy-N-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)acetamide.Reaction of tert-butyl(1-(1-(2-hydroxyacetamido)-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)carbamate(Procedure K) yielded the title product (50%). ¹H NMR (400 MHz, CDCl₃) δ7.66 (br s, 1H), 7.24-7.03 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 7.02-6.76(m, 7H), 6.71 (d, J=7.6 Hz, 1H), 5.29-4.86 (br m, 1H), 4.83 (d, J=16.8Hz, 1H), 4.75 (d, J=17.1 Hz, 1H), 4.42-4.02 (br m, 2H), 3.98 (d, J=15.8Hz, 1H), 3.91 (d, J=16.1 Hz, 1H), 3.72 (br s, 1H), 3.51-3.29 (br m, 1H),3.12 (dd, J=14.1, 5.9 Hz, 1H), 2.30 (s, 3H), 2.24 (s, 3H). ¹³C NMR (101MHz, CDCl₃) δ 173.0, 155.5, 137.6, 136.1, 132.2, 131.5, 129.7, 129.2,129.0, 128.9, 126.7, 126.5, 121.3, 120.7, 110.1, 107.3, 62.0, 56.0,44.9, 41.0, 35.2, 21.24, 21.21.

Synthesis with General Procedure (L).

(S)-2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol

Reaction of 2-fluoro-3-nitro pyridine with(S)-2-amino-3-(p-tolyl)propan-1-ol yielded the product as yellow solid(50%). ¹H NMR (400 MHz, CDCl₃) δ 8.44-8.30 (m, 3H), 7.17 (d, J=8.0 Hz,2H), 7.11 (d, J=7.9 Hz, 2H), 6.66 (dd, J=8.3, 4.5 Hz, 1H), 4.67-4.55 (m,1H), 3.85 (d, J=10.9 Hz, 1H), 3.73 (dd, J=10.6, 6.0 Hz, 1H), 3.11 (s,1H), 2.97 (dddd, J=13.8, 13.8, 13.8, 7.0 Hz, 2H), 2.31 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 155.27, 152.67, 136.33, 135.69, 134.26, 129.36,129.13, 128.34, 112.11, 65.38, 54.96, 37.22, 21.04.

(S)—N-(1-methoxy-3-(p-tolyl)propan-2-yl)-3-nitropyridin-2-amine.Reaction of 2-fluoro-3-nitro pyridine with(S)-1-methoxy-3-(p-tolyl)propan-2-amine yielded the product as yellowsolid (48%). ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.34 (m, 3H), 7.17 (d, J=7.9Hz, 2H), 7.10 (d, J=7.9 Hz, 2H), 6.61 (dd, J=8.1, 4.7 Hz, 1H), 4.83-4.59(m, 1H), 3.48-3.40 (m, 2H), 3.39 (s, 3H), 3.05-2.88 (m, 2H), 2.31 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.71, 152.17, 135.96, 135.28, 134.89,129.34, 129.14, 127.98, 111.64, 72.37, 59.15, 51.90, 37.05, 21.06.

(S)—N-(1-methoxy-3-(p-tolyl)propan-2-yl)-2-nitropyridin-3-amine.Reaction of 2-nitro-3-fluoro pyridine with(S)-1-methoxy-3-(p-tolyl)propan-2-amine yielded the product as yellowsolid (37%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=7.0 Hz, 1H), 7.84 (dd,J=3.6, 1.7 Hz, 1H), 7.34-7.32 (m, 1H), 7.10 (s, 4H), 3.99-3.86 (m, 1H),3.47 (dd, J=4.7, 1.5 Hz, 2H), 3.40 (s, 3H), 3.00 (dd, J=13.8, 6.7 Hz,1H), 2.89 (dd, J=14.0, 6.5 Hz, 1H), 2.31 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 140.77, 140.48, 136.48, 135.10, 133.86, 130.20, 129.40, 129.18,123.72, 73.19, 59.27, 53.92, 37.38, 21.02.

(S)-3-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propoxy)propanenitrile.Reaction of 2-fluoro-3-nitro pyridine with(S)-3-(2-amino-3-(p-tolyl)propoxy)propanenitrile yielded the product asyellow solid (81%). ¹H NMR (400 MHz, CDCl₃) δ 8.44-8.34 (m, 2H), 7.15(dd, J=32.4, 7.8 Hz, 4H), 6.66-6.58 (m, 1H), 4.84-4.69 (m, 1H), 3.69(qt, J=9.5, 4.9 Hz, 2H), 3.55 (qd, J=9.4, 4.3 Hz, 2H), 3.05-2.93 (m,2H), 2.65 (td, J=6.4, 1.3 Hz, 2H), 2.30 (s, 1H). ¹³C NMR (101 MHz,CDCl₃) δ 155.71, 152.02, 136.09, 135.32, 134.60, 129.32, 129.25, 128.05,117.83, 111.91, 70.81, 65.84, 51.63, 36.91, 21.06, 18.85.

(S)—N-methyl-2-((2-nitrophenyl)amino)-3-(p-tolyl)propenamide. Reactionof 1-fluoro-2-nitrobezene with(S)-2-amino-N-methyl-3-(p-tolyl)propanamide yielded the product asyellow solid (36%). ¹H NMR (400 MHz, CDCl₃) δ 8.15 (dd, J=8.6, 1.5 Hz,1H), 7.47-7.39 (m, 1H), 7.21-7.08 (m, 4H), 6.79-6.73 (m, 1H), 6.68 (d,J=8.5 Hz, 1H), 4.18 (dq, J=7.4, 4.6 Hz, 1H), 3.79-3.71 (m, 1H), 3.28(dd, J=14.0, 4.6 Hz, 1H), 3.22-3.15 (m, 1H), 3.10 (dd, J=14.3, 4.6 Hz,1H), 2.79-2.74 (m, 3H), 2.31 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 171.87,143.78, 137.15, 136.51, 132.52, 129.61, 129.34, 129.28, 129.16, 126.77,117.29, 114.56, 60.04, 59.30, 38.56, 36.69, 26.17, 25.22, 21.07.

(S)-1-(azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of 1-fluoro-2-nitrobezene with(S)-2-amino-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-one yielded theproduct as yellow solid (59%). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=6.6Hz, 1H), 8.17 (dd, J=8.5, 1.5 Hz, 1H), 7.49-7.41 (m, 1H), 7.20 (q, J=8.1Hz, 3H), 6.71 (ddd, J=12.5, 6.9, 2.8 Hz, 2H), 4.26-4.19 (m, 1H),4.11-3.89 (m, 2H), 3.74-3.63 (m, 1H), 3.46-3.32 (m, 1H), 3.17 (ddd,J=28.9, 13.6, 6.5 Hz, 2H), 2.35 (s, 3H), 2.15-1.91 (m, 2H). ¹³C NMR (101MHz, CDCl₃) δ 170.03, 143.64, 137.18, 136.39, 132.85, 129.49, 129.24,127.03, 116.22, 113.69, 56.64, 50.69, 48.39, 38.40, 21.12, 15.76.

(S)-2-((2-nitrophenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of 1-fluoro-2-nitrobezene with(S)-2-amino-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-one yielded theproduct as yellow solid (80%). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=7.3Hz, 1H), 8.17 (dd, J=8.5, 1.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.13 (q, J=8.0Hz, 4H), 6.65 (ddd, J=12.2, 6.8, 2.6 Hz, 2H), 4.45 (q, J=7.1 Hz, 1H),3.55-3.38 (m, 2H), 3.32 (tt, J=15.5, 7.6 Hz, 1H), 3.13 (d, J=7.0 Hz,2H), 2.84-2.76 (m, 1H), 2.32 (s, 3H), 1.90-1.58 (m, 4H). ¹³C NMR (101MHz, CDCl₃) δ 169.07, 143.74, 136.86, 136.08, 133.06, 129.32, 129.20,127.15, 115.71, 113.56, 56.92, 46.24, 46.16, 38.96, 26.06, 23.86, 21.07.

(S)-2-((2-nitrophenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of 1-fluoro-2-nitrobezene with(S)-2-amino-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-one yielded theproduct as yellow solid (36%). ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J=7.2Hz, 1H), 8.17 (dd, J=8.5, 1.4 Hz, 1H), 7.39-7.33 (m, 1H), 7.16-7.00 (m,4H), 6.70-6.58 (m, 2H), 4.71 (q, J=7.0 Hz, 1H), 3.67-3.47 (m, 2H),3.43-3.29 (m, 1H), 3.22-3.03 (m, 3H), 2.31 (s, 3H), 1.73-1.39 (m, 5H),1.31-1.13 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 168.83, 143.80, 136.83,135.95, 133.03, 129.38, 129.27, 127.18, 115.66, 113.57, 54.45, 46.49,43.40, 38.99, 26.09, 25.43, 24.30, 21.09.

(S)-1-(3-methoxyazetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of 1-fluoro-2-nitrobezene with(S)-2-amino-1-(3-methoxyazetidin-1-yl)-3-(p-tolyl)propan-1-one yieldedthe product as yellow solid (46%). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (t,J=5.6 Hz, 1H), 8.19-8.08 (m, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.22-7.12 (m,4H), 6.68 (t, J=7.5 Hz, 2H), 4.27-3.99 (m, 2H), 3.99-3.71 (m, 3H),3.58-3.40 (m, 1H), 3.26-3.05 (m, 5H), 2.33 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 170.48, 170.20, 143.53, 137.23, 137.17, 136.47, 136.45, 132.69,132.39, 132.35, 129.62, 129.59, 129.20, 127.01, 116.36, 116.33, 113.69,113.64, 69.04, 68.81, 57.49, 57.38, 56.95, 56.82, 56.01, 55.44, 38.45,38.37, 21.10.

(S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of 1-fluoro-2-nitrobezene with(S)-2-amino-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-oneyielded the product as yellow solid (40%).

methyl(S)-1-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylate.Reaction of 1-fluoro-2-nitrobezene with methyl(S)-1-(2-amino-3-(p-tolyl)propanoyl)azetidine-3-carboxylate yielded theproduct as yellow solid (64%). ¹H NMR (400 MHz, CDCl₃) δ 8.33 (dd,J=11.6, 6.6 Hz, 1H), 8.18-8.05 (m, 1H), 7.50-7.35 (m, 1H), 7.20-7.08 (m,3H), 6.77-6.58 (m, 2H), 4.24-3.99 (m, 3H), 3.88-3.70 (m, 1H), 3.71-3.58(m, 3H), 3.50-3.39 (m, 1H), 3.24-3.14 (m, 1H), 3.08 (ddd, J=15.1, 8.1,4.9 Hz, 1H), 2.88 (d, J=31.0 Hz, 1H), 2.32 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 172.07, 171.86, 170.34, 170.13, 143.44, 137.28, 137.24, 136.51,136.46, 132.60, 132.56, 132.41, 132.40, 129.62, 129.57, 129.19, 127.01,116.44, 116.41, 113.68, 113.63, 56.74, 56.65, 52.91, 52.84, 52.38,52.29, 50.71, 50.68, 38.39, 38.37, 32.26, 32.19, 21.12.

(S)-2-((3-nitropyridin-2-yl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one.Reaction of 2-fluoro-3-nitro pyridine with(S)-2-amino-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-oneyielded the product as yellow solid (76%).

(S)-1-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrileReaction of 2-fluoro-3-nitro pyridine with(S)-1-(2-amino-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile yielded theproduct as yellow solid (73%). ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.34 (m,3H), 7.24-7.09 (m, 4H), 6.73 (ddd, J=11.1, 8.3, 4.6 Hz, 1H), 4.83-4.63(m, 1H), 4.49-4.38 (m, 0.5H), 4.33-3.98 (m, 3H), 3.66 (t, J=8.8 Hz,0.5H), 3.35-2.98 (m, 4H), 2.41-2.33 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ171.96, 171.26, 155.30, 155.16, 151.08, 151.07, 137.70, 137.20, 135.38,135.34, 132.93, 132.83, 129.65, 129.50, 129.16, 129.15, 119.12, 118.75,112.99, 112.72, 53.64, 53.04, 52.89, 52.80, 51.25, 51.00, 38.67, 38.20,21.15, 17.44, 17.11.

(S)-2-((2-nitrophenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid with2-Oxa-6-azaspiro[3.3]heptane hemioxalate yielded the product as yellowsolid (83%). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J=6.6 Hz, 1H), 8.19 (d,J=8.4 Hz, 1H), 7.44 (dd, J=7.7 Hz, 1H), 7.19 (ddd, J=8.0 Hz, 4H), 6.71(dd, J=14.2, 8.1 Hz, 2H), 4.60 (d, J=6.9 Hz, 1H), 4.52 (d, J=7.0 Hz,1H), 4.39 (d, J=6.9 Hz, 1H), 4.29 (d, J=7.0 Hz, 1H), 4.21 (dd, J=12.1,6.5 Hz, 1H), 4.10 (d, J=10.9 Hz, 1H), 3.99 (d, J=10.9 Hz, 1H), 3.43 (d,J=9.5 Hz, 1H), 3.29 (dd, J=13.5, 4.8 Hz, 1H), 3.20 (d, J=9.4 Hz, 1H),3.05 (dd, J=13.5, 7.0 Hz, 1H), 2.91 (d, J=29.9 Hz, 1H), 2.36 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 170.12, 143.36, 137.47, 136.51, 132.79,132.38, 129.54, 129.38, 127.12, 116.46, 113.51, 80.55, 80.32, 59.77,57.82, 56.91, 38.54, 37.71, 21.11.

(S)-1-morpholino-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid withmorpholine yielded the product as yellow solid (68%). ¹H NMR (400 MHz,CDCl₃) δ 8.66 (d, J=7.3 Hz, 1H), 8.15 (dd, J=8.6, 1.4 Hz, 1H), 7.41(ddd, J=8.2, 1.0 Hz, 1H), 7.16-7.07 (m, 4H), 6.73 (d, J=8.5 Hz, 1H),6.66 (ddd, J=7.0, 1.0 Hz, 1H), 4.71 (dd, J=13.8, 7.7 Hz, 1H), 3.69-3.42(m, 5H), 3.39-3.29 (m, 1H), 3.20-2.97 (m, 4H), 2.32 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 169.43, 143.48, 137.13, 136.18, 132.64, 129.50,129.35, 127.20, 115.91, 113.47, 66.56, 65.93, 53.86, 45.90, 42.44,39.16, 21.11.

(S)-1-(4-hydroxypiperidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid with4-hydroxypiperidine hydrochloride yielded the product as yellow solid(86%). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (dd, J=8.5, 1.2 Hz, 1H), 7.42-7.33(m, 1H), 7.15-7.05 (m, 4H), 6.70-6.62 (m, 2H), 4.73 (t, J=6.9 Hz, 1H),4.05-3.94 (m, 1H), 3.87 (dtd, J=11.1, 7.5, 3.8 Hz, 1H), 3.58 (ddd,J=19.5, 14.6, 7.1 Hz, 1H), 3.35-3.19 (m, 2H), 2.98-2.85 (m, 1H), 2.31(s, 3H), 1.89-1.66 (m, 2H), 1.55-1.38 (m, 2H), 1.11-0.95 (m, 1H). ¹³CNMR (101 MHz, CDCl₃) δ 169.20, 169.18, 143.63, 137.03, 136.99, 136.12,136.10, 132.80, 132.77, 132.63, 129.50, 129.43, 129.27, 127.22, 115.90,113.50, 66.46, 54.43, 54.34, 46.84, 42.67, 42.48, 39.60, 39.48, 39.05,38.92, 33.89, 33.76, 33.53, 33.48, 21.08, 8.70.

tert-butyl(S)-6-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid withtert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate yielded theproduct as yellow solid (73%). ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=6.8Hz, 1H), 8.11 (dd, J=14.6, 6.9 Hz, 1H), 7.38 (dd, J=15.5, 7.8 Hz, 1H),7.19-7.10 (m, 4H), 6.65 (t, J=7.7 Hz, 2H), 4.16 (dd, J=12.1, 6.9 Hz,1H), 4.01 (d, J=10.9 Hz, 1H), 3.90 (d, J=10.8 Hz, 1H), 3.83 (d, J=9.3Hz, 1H), 3.73 (d, J=9.4 Hz, 1H), 3.64 (d, J=9.3 Hz, 1H), 3.49 (d, J=9.4Hz, 1H), 3.45 (d, J=9.4 Hz, 1H), 3.23 (dd, J=13.4, 4.9 Hz, 1H), 3.10 (d,J=9.4 Hz, 1H), 2.99 (dd, J=13.4, 7.4 Hz, 1H), 2.32 (s, 3H), 1.35 (s,9H). ¹³C NMR (101 MHz, CDCl₃) δ 169.91, 155.59, 143.31, 137.38, 136.50,132.75, 132.28, 129.55, 129.34, 127.01, 116.37, 113.50, 79.80, 60.30,58.29, 56.50, 38.57, 32.07, 28.24, 21.05, 14.17.

(S)-1-(3-(methoxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid with3-(Methoxymethyl)azetidine hydrochloride yielded the product as yellowsolid (39%). ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 8.16 (d, J=9.1 Hz,1H), 7.77 (dd, J=8.6, 5.3 Hz, 1H), 7.46-7.38 (m, 2H), 7.22-7.14 (m, 4H),6.78-6.62 (m, 2H), 4.29-4.18 (m, 1H), 4.01 (ddd, J=34.0, 9.5 Hz, 1H),3.84-3.56 (m, 1H), 3.43 (dd, J=16.4, 7.5 Hz, 1H), 3.38-3.15 (m, 6H),3.15-3.03 (m, 2H), 2.71-2.44 (m, 2H), 2.34 (d, J=2.4 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 170.59, 170.49, 143.51, 143.48, 137.20, 137.16,136.50, 136.37, 132.68, 132.62, 129.62, 129.57, 129.31, 129.27, 127.07,127.04, 126.87, 126.56, 116.51, 116.41, 116.29, 113.62, 113.56, 111.57,73.78, 73.60, 59.05, 58.95, 56.76, 56.14, 53.46, 53.39, 50.84, 50.78,38.46, 38.34, 28.81, 28.50, 21.12.

(S)-1-(3-hydroxyazetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid with3-hydroxyazetidine, HCl yielded the product as yellow solid (40%).

(S)-1-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile.Reaction of (S)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoic acid withazetidine-3-carbonitrile, HCl yielded the product as yellow solid (45%).¹H NMR (400 MHz, CDCl₃) δ 8.32 (dd, J=15.5, 6.4 Hz, 1H), 8.18 (d, J=8.6Hz, 1H), 7.47 (dd, J=14.1, 7.0 Hz, 1H), 7.31-7.19 (m, 4H), 6.75 (dd,J=8.3, 7.3 Hz, 1H), 6.72-6.67 (m, 1H), 4.31-4.04 (m, 3H), 3.71 (t, J=8.4Hz, 0.5H), 3.50 (t, J=9.1 Hz, 0.5H), 3.37 (dd, J=13.8, 5.0 Hz, 0.5H),3.31-3.01 (m, 4H), 2.38 (d, J=1.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ170.91, 170.52, 143.14, 143.10, 138.23, 138.03, 136.73, 136.67, 132.54,132.41, 132.33, 132.07, 130.18, 129.85, 129.16, 129.10, 127.22, 127.09,118.55, 118.52, 116.97, 116.86, 113.56, 113.36, 57.73, 56.84, 53.77,53.52, 51.60, 51.40, 38.53, 38.27, 21.16, 21.14, 17.52, 17.44.

(S)-1-(3-(hydroxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one.At 0° C., to a solution of methyl(S)-1-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylate(1 eq.) in THF was added lithium borohydride (1 eq.). The mixture wasslowly warmed to room temperature and stirred for overnight. Saturatedsodium bicarbonate aqueous solution was added to quench the reaction.After extraction with ethyl acetate for three times the combined organicphase was concentrated and purified by flash chromatography using 80%ethyl acetate in hexanes as eluent, yielding the product as yellow solid(57%). ¹H NMR (400 MHz, CDCl₃) δ 8.38 (t, J=6.5 Hz, 1H), 8.20-8.12 (m,1H), 7.47-7.37 (m, 1H), 7.24-7.13 (m, 4H), 6.74-6.64 (m, 2H), 4.22(dddd, J=6.7, 6.7, 6.7, 2.2 Hz, 1H), 4.05-3.91 (m, 1H), 3.83-3.72 (m,1H), 3.70-3.36 (m, 4H), 3.24-3.02 (m, 2H), 2.66-2.41 (m, 1H), 2.34 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 170.34, 170.26, 143.58, 143.56, 137.19,136.45, 136.35, 132.85, 132.78, 132.44, 132.37, 129.57, 129.53, 129.33,129.28, 127.10, 127.03, 116.28, 116.23, 113.69, 113.59, 63.80, 63.51,56.50, 56.15, 52.68, 52.67, 50.34, 50.32, 38.47, 38.39, 30.68, 30.45,21.12, 21.10.

(S)-1-(tert-butyl) 3-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate. At room temperature, alcohol (1 eq.),carboxylic acid (1 eq.), EDC HCl (1.1 eq.) and DMAP (1.1 eq.) was mixedin dry DCM and the mixture was stirred at room temperature forovernight. After removing solvent, the residue was purified by flashchromatography using 20% ethyl acetate in hexanes as eluent. Givingproduct as yellow solid (76%). ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.10 (m,2H), 7.49-7.35 (m, 1H), 7.17-7.05 (m, 4H), 6.97 (dd, J=15.5, 8.4 Hz,1H), 6.74-6.59 (m, 1H), 4.33-4.24 (m, 1H), 4.20-3.99 (m, 5H), 3.40-3.27(m, 1H), 2.95 (d, J=6.3 Hz, 2H), 2.31 (s, 3H), 1.44 (s, 9H). ¹³C NMR(101 MHz, CDCl₃) δ 172.43, 155.95, 144.39, 136.75, 136.27, 133.07,132.37, 129.52, 129.10, 127.10, 115.92, 113.92, 79.91, 65.28, 52.37,37.57, 31.99, 28.33, 21.04.

(S)-2-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propyl)isoindoline-1,3-dione.At 0° C., to a solution of alcohol (1 eq.), phthalimide (2 eq.) andtriphenylphosphine (2 eq.) was added DIAD (2 eq.) dropwise. The mixturewas warmed to room temperature and stirred for overnight. After removingsolvent, the residue was purified using 20% ethyl acetate in hexanes aseluent. Giving product as yellow solid (84%). ¹H NMR (400 MHz, CDCl₃) δ8.27 (dd, J=8.3, 1.6 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.06 (dd, J=4.4,1.6 Hz, 1H), 7.86 (ddd, J=6.5, 3.3, 3.3 Hz, 1H), 7.77-7.72 (m, 2H),7.68-7.63 (m, 2H), 7.17 (d, J=7.9 Hz, 2H), 7.10-7.04 (m, 2H), 6.43 (dd,J=8.3, 4.5 Hz, 1H), 5.13 (dddd, J=17.8, 17.8, 8.9, 8.9 Hz, 1H),4.02-3.88 (m, 2H), 3.07-2.90 (m, 2H), 2.27 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 168.36, 155.08, 152.47, 136.29, 135.09, 134.30, 133.88, 133.77,131.88, 129.30, 129.04, 123.58, 123.18, 111.83, 50.87, 41.63, 38.64,21.03.

(S)—N2-(3-nitropyridin-2-yl)-3-(p-tolyl)propane-1,2-diamine. At 0° C.,hydrazine (10 eq.) was added to a solution of starting material (1 eq.)in methanol dropwise. The mixture was warmed to room temperature andstirred for 3 hours. After removing solvent, the residue was purifiedusing 50% ethyl acetate in hexanes as eluent. Giving product as yellowsolid (60%). ¹H NMR (400 MHz, CDCl₃) δ 8.40-8.31 (m, 3H), 7.10 (dd,J=19.7, 8.0 Hz, 4H), 6.60 (dd, J=8.0, 4.8 Hz, 1H), 4.71-4.54 (m, 1H),2.99-2.78 (m, 4H), 2.29 (s, 3H).

(S)-2-hydroxy-N-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propyl)acetamide.To a solution of acid (1 eq.) in dichloromethane was added HATU (1.1eq.), followed by addition of amine (1 eq.) and DIPEA (1.2 eq.). Themixture was stirred at room temperature for overnight. After removingsolvent, the residue was purified using 70% ethyl acetate in hexanes aseluent. Giving product as yellow solid (87%).

(S)-2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propanal. At roomtemperature, to a solution of starting material in dichloromethane wasadded Dess-Martin periodinane (2 eq.). The solution was stirred at roomtemperature for 2 hours. After removing solvent, the residue waspurified using 30% ethyl acetate in hexanes as eluent, giving product asyellow solid (69%). ¹H NMR (400 MHz, CDCl₃) δ 9.66 (s, 1H), 8.42 (d,J=8.3 Hz, 1H), 8.35 (d, J=4.5 Hz, 1H), 7.14 (s, 4H), 6.73 (dd, J=8.3,4.6 Hz, 1H), 4.90-4.73 (m, 1H), 3.32-3.03 (m, 2H), 2.32 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 199.91, 155.12, 151.55, 137.00, 135.32, 132.53,129.70, 129.06, 113.10, 61.59, 34.98, 21.07.

(S)—N1-methyl-N2-(3-nitropyridin-2-yl)-3-(p-tolyl)propane-1,2-diamine.At room temperature, to a solution of aldehyde (1 eq.) was added methylamine (1 eq., solution in ethanol) and sodium triacetoxyborohydride (2eq.). The mixture was stirred at room temperature for 3 hours. Afterremoving solvent, the residue was purified using 80% ethyl acetate inhexanes as eluent, giving product as yellow solid (40%). ¹H NMR (400MHz, CDCl₃) δ 8.41-8.35 (m, 2H), 8.30 (d, J=7.7 Hz, 1H), 7.11 (q, J=8.0Hz, 4H), 6.67-6.59 (m, 1H), 4.86-4.74 (m, 1H), 3.05-2.74 (m, 4H), 2.46(s, 3H), 2.30 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.64, 152.51,136.14, 135.33, 134.43, 129.21, 129.18, 111.88, 54.13, 51.44, 38.68,36.03, 21.04.

(S)-2-hydroxy-N-methyl-N-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propyl)acetamide.To a solution of acid (1 eq.) in dichloromethane was added HATU (1.1eq.), followed by addition of amine (1 eq.) and DIPEA (1.2 eq.). Themixture was stirred at room temperature for overnight. After removingsolvent, the residue was purified using 70% ethyl acetate in hexanes aseluent. Giving product as yellow solid (61%). ¹H NMR (400 MHz, CDCl₃) δ8.38-8.32 (m, 2H), 7.16-7.04 (m, 4H), 6.68-6.56 (m, 1H), 5.02-4.84 (m,1H), 3.97 (q, J=15.4 Hz, 1H), 3.77 (dt, J=13.8, 9.0 Hz, 1H), 3.01-2.83(m, 4H), 2.80 (d, J=7.2 Hz, 3H), 2.28 (d, J=2.5 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 172.57, 172.07, 155.61, 155.35, 152.38, 152.13, 135.40,135.36, 129.53, 129.45, 129.30, 129.22, 129.04, 129.01, 128.91, 128.85,128.11, 112.71, 112.55, 112.07, 111.81, 59.85, 51.85, 51.64, 50.64,50.24, 38.71, 38.62, 33.79, 21.59, 21.04.

Synthesis with General Procedure (M).

(S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol

Reaction of (S)-2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propan-1-olwith palladium on charcoal yielded the product as brown solid.

(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)pyridine-2,3-diamine. Reactionof (S)—N-(1-methoxy-3-(p-tolyl)propan-2-yl)-3-nitropyridin-2-amine withpalladium on charcoal yielded the product as brown solid.

(S)—N3-(1-methoxy-3-(p-tolyl)propan-2-yl)pyridine-2,3-diamine. Reactionof (S)—N-(1-methoxy-3-(p-tolyl)propan-2-yl)-2-nitropyridin-3-amine withpalladium on charcoal yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-N-methyl-3-(p-tolyl)propenamide. Reactionof (S)—N-methyl-2-((2-nitrophenyl)amino)-3-(p-tolyl)propenamide withRaney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-nitrophenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-nitrophenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

methyl(S)-1-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylate.Reaction of methyl(S)-1-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylatewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(3-methoxyazetidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(3-methoxyazetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-3-(2-((2-aminophenyl)amino)-3-(p-tolyl)propyl) 1-(tert-butyl)azetidine-1,3-dicarboxylate. Reaction of (S)-1-(tert-butyl)3-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate with Raney nickel yielded the product asbrown solid.

(S)-2-((2-aminophenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-nitrophenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-morpholino-3-(p-tolyl)propan-1-one(WZ-II-109). Reaction of(S)-1-morpholino-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-one withRaney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-120). Reaction of(S)-1-(3-(hydroxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(4-hydroxypiperidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(4-hydroxypiperidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith Raney nickel yielded the product as brown solid.

tert-butyl(S)-6-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.Reaction of tert-butyl(S)-6-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylatewith Raney nickel yielded the product as brown solid.

(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxyacetamide.Reaction of(S)-2-hydroxy-N-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propyl)acetamidewith palladium on charcoal yielded the product as brown solid.

(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxy-N-methylacetamide.Reaction of(S)-2-hydroxy-N-methyl-N-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propyl)acetamidewith palladium on charcoal yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(3-(methoxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(3-(methoxymethyl)azetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith palladium on charcoal yielded the product as brown solid.

(S)-2-((3-aminopyridin-2-yl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-on.Reaction of(S)-2-((3-nitropyridin-2-yl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith palladium on charcoal yielded the product as brown solid.

(S)-2-((2-aminophenyl)amino)-1-(3-hydroxyazetidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-1-(3-hydroxyazetidin-1-yl)-2-((2-nitrophenyl)amino)-3-(p-tolyl)propan-1-onewith palladium on charcoal yielded the product as brown solid.

(S)-1-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile.Reaction of(S)-1-(2-((2-nitrophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrilewith palladium on charcoal yielded the product as brown solid.

(S)-1-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile.Reaction of(S)-1-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrilewith palladium on charcoal yielded the product as brown solid.

(S)-3-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propoxy)propanenitrile.Reaction of(S)-3-(2-((3-nitropyridin-2-yl)amino)-3-(p-tolyl)propoxy)propanenitrilewith palladium on charcoal yielded the product as brown solid.

Synthesis with General Procedure (N).

(S)-2-((3-((4-methylbenzyl)amino)pyridin-2-yl)amino)-3-(p-tolyl)propan-1-ol

Reaction of (S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-olwith 4-methyl benzyl bromide yielded the product as brown solid (50%).¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J=5.1, 1.3 Hz, 1H), 7.20-7.13 (m,4H), 7.06 (ddd, J=8.1, 8.1, 8.1 Hz, 4H), 6.75 (dd, J=7.6, 1.1 Hz, 1H),6.58 (dd, J=7.6, 5.2 Hz, 1H), 4.39 (d, J=3.9 Hz, 1H), 4.16-4.04 (m, 3H),3.86 (dd, J=10.9, 2.1 Hz, 1H), 3.66 (dd, J=10.9, 7.2 Hz, 1H), 3.05 (s,1H), 3.00-2.93 (m, 1H), 2.81-2.73 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 149.89, 137.17, 136.18, 136.15, 135.37,135.05, 131.53, 129.40, 129.28, 129.06, 127.74, 117.82, 114.15, 68.06,56.58, 48.06, 37.56, 21.17, 21.05.

(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(4-methylbenzyl)pyridine-2,3-diamine.Reaction of(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)pyridine-2,3-diamine with4-methyl benzyl bromide yielded the product as brown solid (8%). ¹H NMR(400 MHz, CDCl₃) δ 7.73 (d, J=4.2 Hz, 1H), 7.29-7.23 (m, 2H), 7.17 (dd,J=13.8, 7.9 Hz, 4H), 7.09 (d, J=7.8 Hz, 2H), 6.79-6.75 (m, 1H), 6.59(dd, J=7.5, 5.1 Hz, 1H), 4.49 (q, J=11.9 Hz, 1H), 4.36 (s, 1H), 4.20 (s,2H), 3.43 (ddd, J=22.2, 9.4, 4.4 Hz, 2H), 3.35 (s, 3H), 3.01 (dd,J=13.4, 5.6 Hz, 1H), 2.94-2.85 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 149.10, 137.32, 137.08, 135.68, 135.57, 131.48,129.48, 129.31, 129.22, 128.98, 127.77, 127.10, 117.07, 113.67, 72.83,58.92, 51.41, 48.12, 37.06, 21.15, 21.08.

(S)—N3-(1-methoxy-3-(p-tolyl)propan-2-yl)-N2-(4-methylbenzyl)pyridine-2,3-diamine.Reaction of(S)—N3-(1-methoxy-3-(p-tolyl)propan-2-yl)pyridine-2,3-diamine with4-methyl benzyl bromide yielded the product as brown solid (12%). ¹H NMR(400 MHz, CDCl₃) δ 7.76 (dd, J=5.0, 1.3 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H),7.18-7.12 (m, 2H), 7.08-7.02 (m, 4H), 6.90 (dd, J=7.5, 1.2 Hz, 1H), 6.59(dd, J=7.5, 5.1 Hz, 1H), 4.51 (s, 2H), 3.55 (s, 1H), 3.39-3.33 (m, 1H),3.33-3.24 (m, 4H), 2.82 (dddd, J=13.7, 13.7, 13.7, 6.6 Hz, 2H), 2.36 (s,3H), 2.30 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 151.28, 138.63, 137.97,137.34, 136.92, 136.64, 135.97, 135.08, 129.61, 129.23, 129.16, 129.13,128.03, 127.10, 120.66, 113.34, 72.83, 65.23, 58.92, 54.58, 45.76,37.14, 29.72, 21.14, 21.04.

(S)—N-methyl-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propenamideReaction of (S)-2-((2-aminophenyl)amino)-N-methyl-3-(p-tolyl)propenamidewith 4-methyl benzyl bromide yielded the product as brown solid (17%).¹H NMR (400 MHz, CDCl₃) δ 7.23-7.06 (m, 4H), 7.02-6.92 (m, 4H), 6.88 (d,J=7.7 Hz, 2H), 6.72 (dt, J=14.9, 7.6 Hz, 1H), 6.26 (d, J=7.9 Hz, 1H),5.64 (d, J=4.6 Hz, 1H), 3.83 (dt, J=29.6, 10.1 Hz, 3H), 3.23-3.07 (m,1H), 3.01 (dd, J=14.3, 8.0 Hz, 1H), 2.57 (d, J=4.9 Hz, 2H), 2.39-2.24(m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 173.65, 142.99, 137.06, 136.64,136.53, 135.21, 133.64, 129.35, 129.20, 129.12, 128.67, 126.04, 123.67,117.74, 110.69, 59.29, 58.67, 38.36, 25.93, 21.19, 21.13.

(S)-1-(azetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (41%).¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J=8.0 Hz, 2H), 7.16 (d, J=6.0 Hz,4H), 7.10 (d, J=7.9 Hz, 2H), 6.83 (td, J=7.7, 1.7 Hz, 1H), 6.76-6.65 (m,2H), 6.59 (t, J=9.1 Hz, 1H), 4.17 (s, 2H), 4.03-3.81 (m, 5H), 3.76 (td,J=8.8, 6.4 Hz, 1H), 3.38 (dt, J=15.0, 7.6 Hz, 1H), 3.06-2.90 (m, 2H),2.37 (s, 3H), 2.33 (s, 3H), 2.12-1.90 (m, 2H). ¹³C NMR (101 MHz, CDCl₃)δ 172.62, 139.59, 136.62, 136.57, 136.36, 134.51, 129.32, 129.17,129.09, 127.45, 121.83, 118.27, 116.90, 111.67, 56.49, 49.84, 48.03,47.71, 39.20, 21.14, 21.10, 15.38.

(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (23%).¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J=8.0 Hz, 2H), 7.14 (dd, J=7.8, 4.1Hz, 4H), 7.06 (d, J=7.8 Hz, 2H), 6.81 (td, J=7.7, 1.4 Hz, 1H), 6.73 (dd,J=7.7, 1.3 Hz, 1H), 6.63 (td, J=7.5, 1.2 Hz, 1H), 6.56 (dt, J=4.5, 2.3Hz, 1H), 4.21-3.93 (m, 5H), 3.49-3.33 (m, 2H), 3.20-3.07 (m, 1H),3.02-2.90 (m, 2H), 2.87-2.78 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H),1.83-1.53 (m, 5H). ¹³C NMR (101 MHz, CDCl₃) δ 171.89, 140.17, 136.64,136.52, 136.17, 134.70, 134.44, 129.35, 129.14, 128.96, 127.40, 122.09,117.90, 111.38, 58.75, 47.93, 46.00, 45.70, 39.58, 25.85, 24.00, 21.13,21.05.

(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (29%).¹H NMR (400 MHz, CDCl₃) δ 7.32-6.96 (m, 8H), 6.90-6.69 (m, 2H),6.68-6.45 (m, 2H), 4.36 (s, 1H), 4.17-4.01 (m, 4H), 3.64-3.38 (m, 2H),3.08 (ddd, J=48.2, 28.7, 6.4 Hz, 4H), 2.46-2.22 (m, 6H), 1.63-0.97 (m,8H). ¹³C NMR (101 MHz, CDCl₃) δ 171.84, 140.32, 136.69, 136.50, 136.14,134.76, 134.40, 129.40, 129.13, 129.02, 127.34, 122.28, 118.28, 117.77,111.32, 55.92, 47.88, 46.33, 43.16, 39.79, 25.97, 25.54, 24.41, 21.13,21.06.

methyl(S)-1-(2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylate.Reaction of methyl(S)-1-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylatewith 4-methyl benzyl bromide yielded the product as brown solid (40%).

(S)-1-(3-methoxyazetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-methoxyazetidin-1-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (38%).

(S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (52%).

(S)-1-(tert-butyl)3-(2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate. Reaction of(S)-3-(2-((2-aminophenyl)amino)-3-(p-tolyl)propyl) 1-(tert-butyl)azetidine-1,3-dicarboxylate with 4-methyl benzyl bromide yielded theproduct as brown solid (47%). ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.22 (m,2H), 7.20-7.15 (m, 2H), 7.12-7.05 (m, 4H), 6.85-6.74 (m, 3H), 6.71-6.64(m, 1H), 4.24 (dd, J=11.2, 5.4 Hz, 1H), 4.19 (s, 1H), 4.14-4.08 (m, 1H),4.06 (d, J=7.6 Hz, 3H), 3.83 (dt, J=11.5, 5.8 Hz, 1H), 3.30-3.21 (m,1H), 2.94-2.79 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 1.45 (s, 9H). ¹³CNMR (101 MHz, CDCl₃) δ 172.54, 155.98, 138.60, 136.84, 136.42, 136.26,134.86, 134.27, 129.30, 129.23, 129.17, 127.70, 120.61, 118.98, 114.63,112.39, 79.84, 66.07, 53.39, 48.41, 37.62, 32.01, 28.36, 21.14, 21.04.

(S,E)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((4-(p-tolyl)but-3-en-1-yl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-onewith (E)-1-(4-bromobut-1-en-1-yl)-4-methylbenzene yielded the product asbrown solid (4%).

(S,E)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((4-(p-tolyl)but-3-en-1-yl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-onewith (E)-1-(4-bromobut-1-en-1-yl)-4-methylbenzene yielded the product asbrown solid (6%).

(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith 4-methyl benzyl bromide yielded the product as brown solid (44%).¹H NMR (400 MHz, CDCl₃) δ 7.27-7.22 (m, 2H), 7.19-7.06 (m, 6H),6.88-6.80 (m, 1H), 6.68 (d, J=3.9 Hz, 2H), 6.64 (d, J=7.7 Hz, 1H), 4.60(d, J=7.0 Hz, 1H), 4.53 (d, J=6.9 Hz, 1H), 4.45 (d, J=7.0 Hz, 1H), 4.26(d, J=6.9 Hz, 1H), 4.02 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.4 Hz, 1H),3.86 (d, J=6.4 Hz, 1H), 3.66 (d, J=9.2 Hz, 1H), 3.13 (d, J=9.1 Hz, 1H),3.05 (dd, J=13.0, 4.5 Hz, 1H), 2.89 (dd, J=12.9, 8.2 Hz, 1H), 2.37 (s,3H), 2.33 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 172.71, 139.62, 136.79,136.57, 136.44, 134.34, 134.27, 129.34, 129.23, 129.10, 127.55, 122.08,118.33, 116.92, 111.87, 80.65, 80.46, 58.99, 57.02, 56.82, 48.12, 39.38,37.36, 21.14, 21.07.

(2S)-2-((2-((cyclopropyl(p-tolyl)methyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-ol.At room temperature, (S)-2-((2-aminophenyl)amino)-3-(p-tolyl)propan-1-ol(1.2 g, 4.69 mmol, 1 eq.), cyclopropyl(p-tolyl)methanol (0.91 g, 5.63mmol, 1.2 eq.), pTSA (0.36 g, 1.88 mmol, 0.4 eq.) and magnesium sulfate(1.7 g, 14.07 mmol, 3 eq.) were mixed in toluene. The mixture wasrefluxed for 3 hours. After filtering off magnesium sulfate, solvent wasremoved under reduced pressure and the residue was purified by flashchromatography using 30% ethyl acetate in hexanes as eluent. Givingproduct as brown solid (13%).

Synthesis with General Procedure (O).

(2S)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one

Reaction of(S)-2-((2-aminophenyl)amino)-1-(azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(18%).

(2S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(11%).

(2S)-1-morpholino-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-morpholino-3-(p-tolyl)propan-1-one with1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(26%). ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.06 (m, 8H), 6.77-6.66 (m, 2H),6.60-6.53 (m, 1H), 6.38 (t, J=8.5 Hz, 1H), 4.45-4.24 (m, 2H), 3.74-3.33(m, 5H), 3.24-2.75 (m, 7H), 2.37-2.25 (m, 6H), 1.43-1.23 (m, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 172.47, 172.46, 142.68, 142.11, 140.00, 139.32,136.51, 136.46, 136.37, 136.25, 134.79, 134.43, 133.78, 133.35, 129.41,129.26, 129.21, 129.18, 125.71, 125.66, 123.29, 122.49, 119.90, 118.10,117.67, 117.56, 112.83, 112.33, 66.69, 66.66, 66.05, 55.52, 55.38,53.13, 52.85, 45.83, 45.77, 42.29, 42.26, 39.99, 39.67, 25.14, 24.88,21.07, 21.06.

(2S)-1-(3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene with1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(29%).

N2-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(1-(p-tolyl)ethyl)pyridine-2,3-diamine.Reaction of(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)pyridine-2,3-diamine with1-(1-bromoethyl)-4-methylbenzene with 1-(1-bromoethyl)-4-methylbenzeneyielded the product as brown solid (10%). ¹H NMR (400 MHz, CDCl₃) δ 7.65(dd, J=5.0, 1.3 Hz, 1H), 7.20-7.09 (m, 8H), 6.54 (dd, J=7.6, 1.2 Hz,1H), 6.45 (dd, J=7.6, 5.0 Hz, 1H), 4.42 (dt, J=12.8, 5.6 Hz, 3H), 3.49(ddd, J=23.5, 9.4, 4.4 Hz, 2H), 3.40 (s, 3H), 3.05-2.93 (m, 2H), 2.35(s, 3H), 2.34 (s, 3H), 1.50 (d, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 149.21, 141.40, 137.11, 136.60, 135.66, 135.60, 130.38, 129.54,129.33, 129.03, 125.75, 118.56, 113.71, 73.16, 58.97, 52.99, 51.53,36.93, 25.17, 21.11.

(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(18%). ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.00 (m, 8H), 6.78-6.55 (m, 3H),6.48-6.35 (m, 1H), 4.65-4.49 (m, 2H), 4.47-4.22 (m, 3H), 4.07-3.93 (m,2H), 3.91-3.73 (m, 1H), 3.69-3.46 (m, 1H), 3.28-3.02 (m, 2H), 2.98-2.85(m, 1H), 2.33 (dd, J=9.6, 3.7 Hz, 6H), 1.40 (dd, J=34.0, 6.6 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 173.08, 172.91, 142.53, 142.10, 139.44,138.58, 136.64, 136.60, 136.41, 136.35, 134.64, 134.44, 134.12, 133.87,129.43, 129.40, 129.25, 129.22, 129.19, 129.17, 125.77, 125.70, 122.69,121.97, 118.47, 118.03, 117.75, 116.90, 113.22, 112.69, 80.65, 80.60,80.55, 80.48, 59.00, 58.93, 57.28, 57.04, 57.01, 56.91, 53.12, 52.90,39.51, 39.39, 37.36, 37.30, 25.09, 25.01, 21.08, 21.07.

(2S)-1-(4-hydroxypiperidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(4-hydroxypiperidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(26%). ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.01 (m, 8H), 6.80-6.67 (m, 2H),6.63-6.49 (m, 1H), 6.41-6.26 (m, 1H), 4.40 (d, J=6.3 Hz, 1H), 4.29-4.18(m, 1H), 4.01-3.89 (m, 1H), 3.81-3.62 (m, 1H), 3.55-3.22 (m, 2H),3.11-2.73 (m, 3H), 2.38-2.23 (m, 6H), 1.66 (ddd, J=26.7, 22.1, 6.5 Hz,2H), 1.43-1.20 (m, 4H), 1.16-0.49 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ172.58, 172.39, 172.36, 172.28, 142.83, 142.78, 142.23, 142.22, 140.22,139.45, 136.38, 136.35, 136.30, 136.27, 136.19, 136.18, 135.03, 134.69,134.68, 134.03, 134.00, 133.56, 129.48, 129.45, 129.41, 129.25, 129.19,129.16, 125.73, 125.59, 123.30, 123.23, 122.40, 122.35, 120.27, 120.22,118.24, 117.56, 117.49, 117.33, 117.27, 112.74, 112.70, 112.25, 112.12,67.24, 66.92, 66.56, 66.17, 56.11, 56.01, 55.88, 55.78, 53.13, 52.87,52.85, 42.94, 42.55, 42.40, 42.16, 39.97, 39.91, 39.77, 39.72, 39.41,39.18, 38.92, 34.18, 34.06, 33.91, 33.79, 33.67, 33.65, 33.59, 25.21,25.17, 25.01, 24.99, 21.08.

tert-butyl6-((2S)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.Reaction of tert-butyl(S)-6-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylatewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(20%). ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.06 (m, 8H), 6.82-6.54 (m, 3H),6.42 (dd, J=17.8, 7.7 Hz, 1H), 4.49-4.29 (m, 1H), 4.04-3.43 (m, 10H),3.17 (ddd, J=24.5, 13.3, 5.9 Hz, 2H), 2.99-2.87 (m, 1H), 2.34 (dd,J=13.7, 7.3 Hz, 6H), 1.48-1.20 (m, 12H). ¹³C NMR (101 MHz, CDCl₃) δ173.03, 172.85, 155.72, 155.71, 142.55, 142.13, 139.38, 138.53, 136.68,136.62, 136.37, 136.32, 134.61, 134.40, 134.11, 133.88, 133.71, 132.51,129.61, 129.43, 129.25, 125.79, 125.71, 123.87, 122.68, 121.96, 119.45,118.33, 118.07, 117.81, 116.83, 115.44, 114.55, 113.22, 112.72, 79.89,79.88, 60.41, 59.59, 59.51, 57.88, 57.68, 57.23, 56.83, 53.12, 52.91,39.49, 39.37, 31.79, 31.74, 28.31, 25.07, 25.01, 21.07, 14.22.

2-hydroxy-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamide.Reaction of(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxyacetamidewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(17%). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=4.3 Hz, 1H), 7.13 (dd,J=22.4, 7.1 Hz, 8H), 6.57-6.32 (m, 2H), 4.74 (s, 1H), 4.29 (dd, J=14.4,7.5 Hz, 2H), 4.00 (s, 2H), 3.56-3.34 (m, 3H), 2.30 (d, J=2.9 Hz, 6H),1.44 (d, J=6.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 172.89, 149.17,141.20, 136.69, 136.15, 134.80, 129.35, 129.22, 125.73, 118.75, 113.78,62.11, 53.22, 52.77, 44.41, 38.83, 29.70, 24.93, 21.04.

2-hydroxy-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamide.Reaction of(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxyacetamidewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(17%). ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=4.1 Hz, 1H), 7.28-6.96 (m,8H), 6.57-6.34 (m, 2H), 4.41-4.17 (m, 2H), 4.05 (s, 2H), 3.62-3.38 (m,2H), 2.31 (s, 6H), 1.48 (d, J=6.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ173.44, 148.74, 140.96, 136.65, 136.28, 134.43, 129.34, 129.24, 125.67,118.78, 113.87, 62.04, 52.93, 44.41, 44.22, 38.47, 29.71, 25.07, 21.09.

2-hydroxy-N-methyl-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamide.Reaction of(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxy-N-methylacetamidewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(8%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (M, 1H), 7.28-7.05 (m, 8H),6.56-6.35 (m, 2H), 4.79-4.30 (m, 3H), 4.18-3.80 (m, 3H), 3.48-2.87 (m,5H), 2.82-2.74 (m, 3H), 2.32 (d, J=9.0 Hz, 6H), 1.52 (dd, J=10.4, 6.7Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 173.31, 148.91, 141.46, 136.68,135.91, 135.10, 129.32, 129.24, 129.16, 125.77, 117.72, 113.31, 59.74,52.96, 51.96, 50.57, 39.01, 33.65, 25.06, 21.08.

2-hydroxy-N-methyl-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamide.Reaction of(S)—N-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propyl)-2-hydroxy-N-methylacetamidewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(8%). ¹H NMR (400 MHz, CDCl₃) δ 7.64-7.43 (m, 1H), 7.26-7.03 (m, 8H),6.50-6.32 (m, 2H), 4.62 (d, J=32.6 Hz, 1H), 4.41-4.26 (m, 1H), 4.21-3.88(m, 3H), 3.35-2.72 (m, 7H), 2.35-2.24 (m, 6H), 1.48 (ddd, J=22.5, 15.4,9.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 173.42, 148.72, 141.45, 136.53,135.97, 134.80, 129.30, 129.19, 129.15, 125.73, 117.75, 113.30, 59.80,53.07, 52.01, 50.67, 38.56, 33.62, 29.71, 25.33, 21.10.

(2S)-1-(3-(methoxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-(methoxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(58%). ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.02 (m, 8H), 6.86-6.54 (m, 3H),6.39 (dd, J=16.0, 7.8 Hz, 1H), 4.36 (dd, J=36.9, 5.8 Hz, 1H), 4.15-3.78(m, 4H), 3.74-3.38 (m, 2H), 3.34-2.83 (m, 7H), 2.64-2.42 (m, 1H), 2.32(dt, J=33.8, 16.8 Hz, 6H), 1.48-1.15 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ173.20, 173.05, 172.94, 142.63, 142.61, 142.23, 142.21, 139.48, 139.34,138.74, 138.68, 136.40, 136.39, 136.33, 136.32, 136.25, 136.22, 134.78,134.57, 134.19, 134.16, 134.02, 133.91, 129.50, 129.47, 129.37, 129.34,129.25, 129.24, 129.21, 129.20, 125.77, 125.71, 125.69, 122.57, 122.41,121.92, 121.81, 118.55, 118.35, 117.95, 117.80, 117.76, 117.15, 116.98,113.03, 112.99, 112.60, 112.50, 74.30, 74.20, 74.18, 74.16, 59.01,58.96, 58.95, 56.82, 56.77, 56.40, 56.39, 53.15, 52.95, 52.91, 52.68,52.61, 52.50, 50.09, 50.03, 49.98, 49.94, 39.46, 39.35, 39.22, 39.05,28.42, 28.35, 28.09, 28.04, 25.19, 25.14, 25.07, 25.04, 21.12, 21.08.

(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-one.Reaction of(S)-2-((3-aminopyridin-2-yl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(13%). ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=3.4 Hz, 1H), 7.24-7.00 (m,8H), 6.51-6.40 (m, 2H), 5.00 (d, J=8.4 Hz, 1H), 4.73 (ddd, J=9.6, 9.6,5.3 Hz, 1H), 4.65 (dd, J=6.3 Hz, 1H), 4.62 (d, J=7.0 Hz, 1H), 4.56 (d,J=6.8 Hz, 1H), 4.34 (ddd, J=13.1, 13.1, 6.7 Hz, 3H), 4.07 (d, J=10.7 Hz,1H), 3.93 (d, J=10.7 Hz, 1H), 3.19 (dd, J=11.4, 5.7 Hz, 2H), 3.02-2.93(m, 1H), 2.35 (s, 3H), 2.29 (s, 3H), 1.51 (d, J=6.6 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 173.27, 147.69, 141.27, 136.50, 136.42, 136.15,134.48, 130.85, 129.44, 129.33, 128.96, 125.74, 117.88, 114.64, 80.95,80.42, 59.36, 56.90, 53.47, 53.22, 52.47, 39.31, 37.44, 25.32, 21.10,21.06.

(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-one.Reaction of(S)-2-((3-aminopyridin-2-yl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(13%). ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=4.4 Hz, 1H), 7.23-7.05 (m,8H), 6.40 (dd, J=7.5, 5.1 Hz, 1H), 6.28 (d, J=7.3 Hz, 1H), 5.72 (d,J=6.5 Hz, 1H), 4.64 (s, 1H), 4.53 (d, J=6.9 Hz, 1H), 4.40 (d, J=9.3 Hz,1H), 4.30 (d, J=6.9 Hz, 1H), 4.08-4.02 (m, 2H), 3.92 (d, J=10.8 Hz, 1H),3.29 (dd, J=12.6, 4.9 Hz, 1H), 3.21 (d, J=9.2 Hz, 1H), 3.14-3.05 (m,1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.34 (d, J=6.5 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 173.95, 147.40, 141.80, 136.44, 136.29, 135.34, 134.54,130.49, 129.46, 129.24, 128.96, 125.63, 117.09, 114.23, 80.90, 80.40,59.43, 57.00, 53.47, 53.11, 52.79, 38.76, 37.46, 25.10, 21.10, 21.08.

(2S)-1-(3-hydroxyazetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-one.Reaction of(S)-2-((2-aminophenyl)amino)-1-(3-hydroxyazetidin-1-yl)-3-(p-tolyl)propan-1-onewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(23%).

1-((2S)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propanoyl)azetidine-3-carbonitrile.Reaction of(S)-1-(2-((2-aminophenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrilewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(27%). ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.08 (m, 8H), 6.81-6.39 (m, 4H),4.48-4.28 (m, 1H), 4.20-4.00 (m, 2H), 3.96-3.73 (m, 2H), 3.66-3.52 (m,1H), 3.32 (dt, J=14.8, 8.6 Hz, 0.5H), 3.19-2.90 (m, 3H), 2.42-2.28 (m,6H), 1.48-1.31 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 173.51, 173.38,173.26, 173.01, 142.51, 142.30, 142.03, 141.96, 139.45, 138.61, 138.26,137.39, 137.34, 137.25, 137.16, 137.03, 136.56, 136.50, 136.41, 134.61,134.14, 134.13, 134.04, 133.97, 133.85, 133.82, 133.60, 129.61, 129.58,129.56, 129.49, 129.29, 129.26, 129.25, 129.24, 129.16, 125.83, 125.78,125.70, 125.68, 123.07, 122.36, 122.26, 121.54, 119.09, 118.84, 118.78,118.77, 118.68, 118.67, 118.61, 118.16, 117.85, 116.99, 116.64, 115.21,114.18, 113.44, 112.79, 60.43, 57.80, 57.51, 57.36, 57.06, 53.15, 53.13,53.04, 52.94, 52.65, 52.58, 51.10, 51.04, 50.88, 50.83, 39.48, 39.31,39.12, 39.02, 24.99, 24.82, 21.14, 21.12, 21.09, 17.33, 17.28, 16.96,16.92.

1-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propanoyl)azetidine-3-carbonitrile.Reaction of(S)-1-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrilewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(7%). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.45 (m, 1H), 7.24-7.00 (m, 8H),6.52-6.40 (m, 2H), 4.89 (dt, J=41.6, 13.5 Hz, 1H), 4.73-4.49 (m, 1.5H),4.36 (q, J=6.3 Hz, 0.5H), 4.26-4.05 (m, 1H), 4.00-3.93 (m, 1H), 3.62(dd, J=21.3, 12.5 Hz, 2H), 3.31-2.91 (m, 4H), 2.43-2.22 (m, 6H), 1.52(d, J=6.6 Hz, 3H).

1-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propanoyl)azetidine-3-carbonitrile.Reaction of(S)-1-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrilewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(7%). ¹H NMR (400 MHz, CDCl₃) δ 7.67-7.40 (m, 1H), 7.21-7.04 (m, 8H),6.52-6.33 (m, 1H), 5.28 (t, J=7.6 Hz, 1H), 4.74-4.45 (m, 1H), 4.24-4.06(m, 2H), 3.97 (d, J=3.5 Hz, 1H), 3.61 (dd, J=21.2, 12.5 Hz, 2H), 3.23(ddd, J=22.3, 15.1, 12.2 Hz, 1H), 3.11-2.94 (m, 1H), 2.84 (dd, J=23.1,11.9 Hz, 1H), 2.40-2.27 (m, 6H), 1.42 (t, J=7.5 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 174.76, 174.20, 171.38, 171.27, 171.16, 155.05, 147.46,147.38, 141.53, 141.47, 137.64, 137.30, 136.61, 136.47, 136.44, 135.97,135.69, 134.07, 133.76, 133.17, 132.80, 130.60, 130.56, 129.60, 129.43,129.29, 129.23, 129.16, 129.12, 129.09, 125.64, 119.19, 119.07, 118.63,117.69, 117.60, 114.88, 114.67, 80.12, 80.06, 60.40, 53.67, 53.20,53.10, 53.02, 52.80, 52.77, 52.75, 52.65, 52.01, 51.80, 51.03, 50.89,50.79, 39.35, 39.30, 38.74, 38.44, 28.33, 25.11, 21.15, 21.11, 21.07,17.28, 17.15, 17.07, 16.77, 14.21.

(2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-ol.Reaction of (S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-olwith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(11%). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J=5.1, 1.4 Hz, 1H), 7.20-7.07(m, 8H), 6.53-6.49 (m, 1H), 6.44 (dd, J=7.6, 5.1 Hz, 1H), 4.47-4.32 (m,1H), 4.22 (q, J=6.6 Hz, 1H), 4.08 (s, 1H), 3.91 (dd, J=11.0, 1.9 Hz,1H), 3.70 (dd, J=10.9, 7.4 Hz, 1H), 3.03 (dd, J=13.9, 5.4 Hz, 1H), 2.81(dd, J=13.8, 9.7 Hz, 1H), 2.38-2.30 (m, 6H), 1.35 (d, J=6.6 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 149.84, 141.06, 136.79, 136.24, 135.89, 135.28,130.59, 129.49, 129.37, 129.12, 125.70, 119.49, 114.13, 68.35, 56.87,53.15, 37.53, 24.87, 21.09, 21.07.

(2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-ol.Reaction of (S)-2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propan-1-olwith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(9%). ¹H NMR (400 MHz, CDCl₃) δ 7.49 (dd, J=5.1, 1.5 Hz, 1H), 7.19-7.10(m, 4H), 7.05 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 6.50 (d, J=7.7Hz, 1H), 6.42 (dd, J=7.6, 5.1 Hz, 1H), 4.53 (s, 1H), 4.32 (q, J=6.5 Hz,1H), 4.06 (s, 1H), 3.91 (dd, J=10.9, 2.0 Hz, 1H), 3.71 (dd, J=10.8, 7.6Hz, 1H), 3.06 (dd, J=13.8, 5.0 Hz, 1H), 2.77 (dd, J=13.8, 10.0 Hz, 1H),2.31 (d, J=6.2 Hz, 6H), 1.42 (d, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 150.23, 140.95, 136.65, 136.42, 135.82, 135.04, 130.31, 129.55,129.29, 129.18, 125.65, 119.30, 114.17, 68.55, 56.94, 52.68, 37.60,25.17, 21.10, 21.08.

3-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propoxy)propanenitrile.Reaction of(S)-3-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propoxy)propanenitrilewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(8%). ¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J=5.0, 1.5 Hz, 1H), 7.24-7.20(m, 4H), 7.17-7.10 (m, 4H), 6.57 (dd, J=6.1, 1.6 Hz, 1H), 6.48-6.43 (m,1H), 4.52 (s, 2H), 4.37 (q, J=6.6 Hz, 1H), 3.85 (s, 1H), 3.71-3.62 (m,2H), 3.60-3.52 (m, 2H), 3.12-3.03 (m, 1H), 3.01-2.91 (m, 1H), 2.63-2.56(m, 2H), 2.37-2.24 (m, 6H), 1.52 (d, J=6.6 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 149.02, 141.54, 137.01, 136.61, 135.76, 135.63, 130.52, 129.44,129.35, 129.12, 125.82, 118.77, 113.76, 71.12, 65.55, 53.33, 51.53,37.23, 25.08, 21.10, 18.90.

3-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propoxy)propanenitrile.Reaction of(S)-3-(2-((3-aminopyridin-2-yl)amino)-3-(p-tolyl)propoxy)propanenitrilewith 1-(1-bromoethyl)-4-methylbenzene yielded the product as brown solid(8%). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (ddd, J=25.8, 5.0, 1.3 Hz, 1H),7.17 (ddd, J=21.8, 7.5, 3.1 Hz, 8H), 6.79-6.59 (m, 1H), 6.49 (ddd,J=12.2, 8.6, 2.9 Hz, 1H), 4.56-4.34 (m, 3H), 3.75-3.52 (m, 5H),3.13-2.97 (m, 3H), 2.61 (dt, J=9.3, 6.2 Hz, 2H), 2.34 (d, J=5.5 Hz, 6H),1.51 (d, J=6.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 149.01, 148.68,141.46, 136.94, 136.71, 136.58, 135.79, 135.71, 135.60, 135.43, 131.86,130.35, 129.48, 129.40, 129.34, 129.13, 129.09, 125.78, 118.69, 118.18,116.53, 113.82, 113.74, 71.43, 71.10, 65.58, 65.53, 53.10, 51.49, 51.42,38.59, 37.11, 36.98, 25.15, 21.11, 21.08, 18.94, 18.91, 14.74.

Synthesis with General Procedure (P).

(S)-2-(2-imino-1-(4-methylbenzyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propan-1-ol(WZ-I-30-3)

Reaction of(S)-2-((3-((4-methylbenzyl)amino)pyridin-2-yl)amino)-3-(p-tolyl)propan-1-olwith cyanogen bromide yielded product as off white solid (50%). ¹H NMR(400 MHz, CDCl₃) δ 7.87 (dd, J=5.2, 1.0 Hz, 1H), 7.10 (t, J=7.3 Hz, 4H),6.99 (dd, J=13.0, 7.9 Hz, 4H), 6.89 (dd, J=7.6, 1.0 Hz, 1H), 6.82 (dd,J=7.7, 5.3 Hz, 1H), 5.90 (s, 2H), 5.07-4.81 (m, 3H), 4.04 (s, 2H), 3.29(d, J=8.0 Hz, 2H), 2.31 (s, 3H), 2.25 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 153.52, 144.90, 139.53, 137.87, 135.78, 134.65, 131.51, 129.66,129.22, 128.96, 126.82, 125.44, 116.46, 112.87, 62.83, 57.97, 45.24,33.43, 21.14, 21.08. HRMS (ESI-TOF) calculated for C24H26N4O [M+H]⁺387.2185, found: 387.2200. [α]_(D) ²⁰−120 (c 0.980, CHCl₃).

(S)-3-(1-methoxy-3-(p-tolyl)propan-2-yl)-1-(4-methylbenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-imine(WZ-I-81). Reaction of(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(4-methylbenzyl)pyridine-2,3-diaminewith cyanogen bromide yielded product as brown solid (45%). ¹H NMR (400MHz, CDCl₃) δ 8.15 (dd, J=5.0, 1.1 Hz, 1H), 7.31-7.24 (m, 1H), 7.12-7.04(m, 7H), 6.92 (d, J=7.9 Hz, 2H), 5.77 (d, J=16.3 Hz, 1H), 5.70-5.54 (m,2H), 4.20-4.07 (m, 1H), 3.84 (dd, J=10.7, 3.0 Hz, 1H), 3.47 (s, 3H),3.41-3.33 (m, 1H), 3.28 (dd, J=13.9, 7.3 Hz, 1H), 2.30 (s, 3H), 2.22 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 151.23, 143.44, 142.79, 138.20, 136.46,132.59, 130.25, 129.62, 129.19, 128.96, 127.68, 123.60, 118.89, 117.39,71.71, 59.45, 56.59, 47.77, 33.41, 21.15, 21.03. HRMS (ESI-TOF)calculated for C25H28N4O [M+H]⁺ 401.2341, found: 401.2344.

(S)-1-(1-methoxy-3-(p-tolyl)propan-2-yl)-3-(4-methylbenzyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-imine(WZ-I-89). Reaction of(S)—N2-(1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(4-methylbenzyl)pyridine-2,3-diaminewith cyanogen bromide yielded product (40%). ¹H NMR (400 MHz, CDCl₃) δ8.21 (d, J=4.3 Hz, 1H), 7.95 (br, 1H), 7.20-7.11 (m, 3H), 7.02 (d, J=7.9Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 6.84 (d, J=7.9 Hz, 2H), 5.74 (d, J=16.0Hz, 1H), 5.60 (d, J=16.0 Hz, 1H), 4.01 (dd, J=10.9, 4.3 Hz, 1H), 3.92(dd, J=10.9, 2.6 Hz, 1H), 3.41 (s, 3H), 3.38-3.33 (m, 1H), 3.23 (dd,J=14.4, 5.5 Hz, 1H), 2.28 (s, 3H), 2.19 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 150.86, 143.23, 143.12, 137.60, 136.38, 132.51, 130.87, 129.31,129.25, 128.66, 127.82, 118.66, 73.48, 59.25, 58.67, 44.70, 34.20,21.16, 21.04. HRMS (ESI-TOF) calculated for C25H28N4O [M+H]+ 401.2341,found: 401.2341.

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methyl-3-(p-tolyl)propenamide(WZ-I-236). Reaction of(S)—N-methyl-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propenamidewith cyanogen bromide yielded product as brown solid (25%). ¹H NMR (400MHz, CDCl₃) δ 9.01 (d, J=4.3 Hz, 1H), 8.34-8.20 (m, 1H), 7.78 (dd,J=8.8, 1.5 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.57 (d, J=1.3 Hz, 1H), 7.41(d, J=7.9 Hz, 1H), 7.18 (d, J=7.9 Hz, 2H), 6.99-6.89 (m, 3H), 6.78 (d,J=7.9 Hz, 2H), 6.37 (d, J=7.9 Hz, 2H), 5.63 (dd, J=7.9, 1.5 Hz, 1H),5.39 (d, J=16.8 Hz, 1H), 5.08 (dd, J=22.4, 10.0 Hz, 2H), 3.89-3.75 (m,2H), 3.66 (d, J=13.0 Hz, 1H), 3.39-3.26 (m, 1H), 2.86 (d, J=4.5 Hz, 2H),2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ165.62, 154.52, 144.38, 138.79, 137.30, 133.69, 132.66, 131.64, 130.90,130.72, 130.02, 129.93, 129.61, 129.30, 129.25, 129.05, 128.73, 125.98,121.16, 117.57, 116.61, 115.92, 63.61, 50.70, 35.14, 29.69, 26.78,21.73, 21.18, 21.11.

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-one(WZ-I-243). Reaction of(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(pyrrolidin-1-yl)-3-(p-tolyl)propan-1-onewith cyanogen bromide yielded the product as off white solid (68%). ¹HNMR (400 MHz, CDCl₃) δ 7.67 (d, J=7.7 Hz, 1H), 7.31-7.17 (m, 2H),7.14-6.97 (m, 5H), 6.87 (dd, J=14.2, 7.9 Hz, 3H), 6.35 (s, 1H), 5.87 (d,J=16.7 Hz, 1H), 5.21 (d, J=16.7 Hz, 1H), 4.19 (s, 1H), 3.63-3.38 (m,4H), 3.07 (dd, J=16.7, 7.1 Hz, 1H), 2.30 (s, 3H), 2.23 (s, 3H),2.04-1.78 (m, 3H), 1.68 (dt, J=21.9, 7.2 Hz, 1H). ¹³C NMR (101 MHz,CDCl₃) δ 164.86, 150.12, 137.90, 136.53, 131.64, 130.11, 129.88, 129.71,129.51, 129.12, 128.77, 127.10, 124.14, 110.46, 58.76, 47.21, 47.08,46.80, 34.57, 26.26, 23.75, 21.20, 21.15. HRMS (ESI-TOF) calculated forC₂₉H₃₂N₄O [M+H]⁺ 453.2654, found: 453.2650. [α]_(D) ²⁰−212 (c 1.165,CHCl₃).

(S)-1-(azetidin-1-yl)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-I-244). Reaction of(S)-1-(azetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-onewith cyanogen bromide yielded the product as off white solid (63%). ¹HNMR (400 MHz, CDCl₃) δ 7.63 (d, J=7.8 Hz, 1H), 7.33-7.19 (m, 2H), 7.08(d, J=7.5 Hz, 1H), 7.01 (dd, J=11.6, 8.0 Hz, 4H), 6.83 (dt, J=14.4, 7.0Hz, 4H), 6.34 (dd, J=10.0, 6.3 Hz, 1H), 5.85 (t, J=17.2 Hz, 1H), 5.18(d, J=16.7 Hz, 1H), 4.98-4.79 (m, 1H), 4.12 (td, J=9.7, 6.5 Hz, 1H),4.00-3.85 (m, 2H), 3.56-3.31 (m, 2H), 2.28 (s, 3H), 2.22 (s, 3H),2.18-2.05 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 166.07, 149.94, 137.85,136.53, 131.44, 130.10, 129.86, 129.58, 129.50, 129.12, 128.53, 126.99,124.21, 112.93, 110.54, 56.77, 51.29, 48.80, 47.21, 33.91, 21.21, 21.15,15.60. HRMS (ESI-TOF) calculated for C28H30N4O [M+H]⁺ 439.2492, found:439.2503. [α]_(D) ²⁰−213 (c 1.095, CHCl₃).

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-one(WZ-I-249). Reaction of(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(piperidin-1-yl)-3-(p-tolyl)propan-1-onewith cyanogen bromide yielded the product as off white solid (69%). ¹HNMR (400 MHz, CDCl₃) δ 7.66 (d, J=7.8 Hz, 1H), 7.30-7.13 (m, 2H),7.10-6.98 (m, 5H), 6.88 (dd, J=12.9, 7.9 Hz, 4H), 6.51 (d, J=4.5 Hz,1H), 5.77 (d, J=16.7 Hz, 1H), 5.22 (d, J=16.7 Hz, 1H), 3.70-3.37 (m,6H), 2.29 (s, 3H), 2.23 (s, 3H), 1.65-1.19 (m, 7H), 1.01-0.89 (m, 1H).¹³C NMR (101 MHz, CDCl₃) δ 164.84, 149.94, 137.83, 136.50, 131.88,130.32, 129.92, 129.71, 129.47, 129.10, 128.89, 127.08, 123.89, 112.83,110.21, 57.09, 47.36, 47.06, 44.08, 35.14, 26.41, 25.66, 24.28, 21.21,21.15. HRMS (ESI-TOF) calculated for C30H34N4O [M+H]⁺ 467.2811, found:467.2864. [α]_(D) ²⁰−184 (c 1.025, CHCl₃).

methyl(S)-1-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propanoyl)azetidine-3-carboxylate(WZ-I-283). Reaction of methyl(S)-1-(2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propanoyl)azetidine-3-carboxylatewith cyanogen bromide yielded the product as off white solid (59%). ¹HNMR (400 MHz, CDCl₃) δ 7.57 (t, J=7.4 Hz, 1H), 7.31-7.15 (m, 2H), 7.05(dt, J=14.0, 6.9 Hz, 3H), 6.97 (d, J=7.7 Hz, 2H), 6.85 (q, J=9.8 Hz,4H), 6.42 (dd, J=29.4, 21.5 Hz, 1H), 5.81 (d, J=16.7 Hz, 1H), 5.17 (dt,J=16.9, 7.2 Hz, 2H), 4.76 (dt, J=18.3, 8.8 Hz, 1H), 4.39-4.16 (m, 1H),3.99 (ddd, J=15.1, 9.5, 6.4 Hz, 1H), 3.72-3.55 (m, 3H), 3.53-3.35 (m,3H), 2.29 (s, 3H), 2.23 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 172.28,172.27, 166.77, 166.20, 150.19, 149.96, 137.88, 137.80, 136.71, 136.60,131.32, 131.24, 130.17, 130.05, 130.01, 129.90, 129.54, 129.51, 129.29,129.25, 129.16, 128.77, 128.29, 127.00, 126.93, 124.32, 124.26, 124.00,123.80, 113.35, 112.55, 110.60, 110.37, 57.47, 56.74, 53.85, 53.37,52.38, 52.27, 51.37, 47.19, 47.06, 33.98, 33.84, 32.33, 32.26, 21.19,21.15. HRMS (ESI-TOF) calculated for C30H32N4O3 [M+H]⁺ 497.2547, found:497.2550. [α]_(D) ²⁰−161 (c 1.080, CHCl₃).

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(3-methoxyazetidin-1-yl)-3-(p-tolyl)propan-1-one(WZ-I-298). Reaction of(S)-1-(3-methoxyazetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-onewith cyanogen bromide yielded the product as off white solid (65%). ¹HNMR (400 MHz, CDCl₃) δ 7.61-7.54 (m, 1H), 7.31-7.16 (m, 3H), 7.12-6.96(m, 5H), 6.86 (dt, J=10.8, 9.7 Hz, 3H), 6.34 (d, J=38.9 Hz, 1H),5.86-5.64 (m, 1H), 5.15 (t, J=13.5 Hz, 2H), 4.56 (dd, J=24.7, 6.5 Hz,1H), 4.31 (dd, J=10.7, 6.7 Hz, 1H), 4.24-4.10 (m, 1H), 3.97 (d, J=7.2Hz, 1H), 3.81 (dd, J=10.7, 4.0 Hz, 1H), 3.61 (dd, J=9.4, 4.2 Hz, 1H),3.45 (dd, J=8.1, 3.2 Hz, 2H), 3.23 (dd, J=29.9, 15.0 Hz, 3H), 2.30 (s,3H), 2.23 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.73, 166.16, 150.28,150.04, 137.98, 137.88, 136.67, 136.56, 131.47, 131.42, 129.99, 129.97,129.59, 129.55, 129.34, 129.23, 129.13, 128.90, 128.41, 126.97, 126.90,124.25, 124.22, 123.92, 123.76, 112.52, 110.43, 110.18, 69.01, 58.45,58.22, 56.91, 56.41, 56.11, 55.95, 47.14, 47.02, 34.11, 33.95, 29.69,21.19, 21.14.

(S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-I-300). Reaction of(S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propan-1-oneyielded the product as off white solid (73%). ¹H NMR (400 MHz, CDCl₃) δ7.60 (d, J=7.7 Hz, 1H), 7.54-7.45 (m, 1H), 7.36-7.28 (m, 1H), 7.22-7.17(m, 1H), 7.14-7.02 (m, 3H), 6.96-6.87 (m, 3H), 6.84-6.75 (m, 3H), 6.26(t, J=12.1 Hz, 1H), 5.63 (dd, J=41.4, 16.9 Hz, 1H), 5.42-5.08 (m, 1H),4.74 (t, J=10.0 Hz, 1H), 4.58 (d, J=9.1 Hz, 1H), 4.41 (d, J=9.0 Hz, 1H),3.93-3.26 (m, 10H), 2.31 (s, 3H), 2.27-2.18 (m, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 166.58, 166.42, 149.74, 138.32, 138.10, 136.87, 131.69, 131.36,129.90, 129.87, 129.76, 129.68, 129.37, 129.26, 129.24, 129.19, 128.46,127.92, 126.93, 126.64, 124.67, 124.58, 124.38, 124.20, 113.55, 112.33,110.73, 110.58, 63.38, 63.14, 58.06, 57.60, 56.77, 55.73, 53.47, 47.09,46.83, 46.73, 41.66, 41.61, 33.99, 33.79, 21.18, 21.10. HRMS (ESI-TOF)calculated for C30H33ClN4O2 [M+H]+ 517.2365, found: 517.2364.

(S)-1-(tert-butyl)3-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate (WZ-I-310). Reaction of (S)-1-(tert-butyl)3-(2-((2-((4-methylbenzyl)amino)phenyl)amino)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate with cyanogen bromide yielded the product asoff white solid (67%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=7.3 Hz, 1H),7.33-7.13 (m, 3H), 7.04 (dd, J=23.3, 7.7 Hz, 4H), 6.90 (dd, J=19.3, 7.9Hz, 2H), 6.80 (d, J=6.0 Hz, 2H), 6.20 (s, 1H), 5.90 (d, J=15.2 Hz, 1H),4.74 (s, 2H), 4.21-3.87 (m, 5H), 3.45-3.21 (m, 3H), 2.27 (s, 3H), 2.23(s, 3H), 1.46-1.27 (m, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 172.05, 155.88,137.77, 136.61, 131.57, 130.18, 129.51, 129.36, 128.94, 126.79, 124.00,123.59, 112.42, 110.92, 79.68, 64.29, 57.24, 47.16, 31.85, 28.27, 21.12.HRMS (ESI-TOF) calculated for C34H40N4O4 [M+H]+ 569.3121, found:569.3122. [α]_(D) ²⁰−85 (c 1.385, CHCl₃).

(2S)-1-(azetidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-92). Reaction of(2S)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-oneand cyanogen bromide yielded the product as off white solid (42%). ¹HNMR (400 MHz, CDCl₃) δ 7.59 (dd, J=16.1, 8.1 Hz, 1H), 7.20 (t, J=7.5 Hz,1H), 7.15-6.89 (m, 9H), 6.80-6.63 (m, 2H), 6.47-6.16 (m, 2H), 4.99 (d,J=6.4 Hz, 1H), 4.23-4.11 (m, 1H), 3.98 (dd, J=24.5, 17.2 Hz, 2H),3.59-3.38 (m, 2H), 2.27 (dd, J=35.8, 15.5 Hz, 9H), 1.85 (d, J=6.6 Hz,1.5H), 1.58 (d, J=6.6 Hz, 1.5H). HRMS (ESI-TOF) calculated for C29H32N4O[M+H]+ 453.2649, found: 453.2649.

(2S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-93). Reaction of(2S)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-oneand cyanogen bromide yielded the product as off white solid (43%). ¹HNMR (400 MHz, CDCl₃) δ 7.51 (dd, J=20.5, 12.0 Hz, 1H), 7.28-6.65 (m,11H), 6.16 (d, J=110.1 Hz, 2H), 5.05-4.79 (m, 1H), 4.35 (dd, J=28.0, 8.8Hz, 1H), 4.08-3.22 (m, 9H), 2.31 (dd, J=20.2, 11.4 Hz, 6H), 1.75 (dt,J=15.5, 8.0 Hz, 3H). HRMS (ESI-TOF) calculated for C31H35ClN4O2 [M+H]+531.2521, found: 531.2514.

(S,E)-1-(3-(chloromethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-3-(4-(p-tolyl)but-3-en-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-98). Reaction of(S,E)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((4-(p-tolyl)but-3-en-1-yl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (55%). HRMS(ESI-TOF) calculated for C33H37ClN4O2 [M+H]+ 557.2678, found: 557.2674.

(S,E)-1-(azetidin-1-yl)-2-(2-imino-3-(4-(p-tolyl)but-3-en-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-104). Reaction of(S,E)-1-(azetidin-1-yl)-3-(p-tolyl)-2-((2-((4-(p-tolyl)but-3-en-1-yl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as brown solid (47%). HRMS(ESI-TOF) calculated for C31H34N4O [M+H]+ 479.2805, found: 479.2806.

(2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-morpholino-3-(p-tolyl)propan-1-one(WZ-II-124). Reaction of(2S)-1-morpholino-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (43%). ¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, J=26.2, 14.9 Hz, 1H), 7.22-6.87 (m,7H), 6.82 (d, J=7.9 Hz, 1H), 6.69 (dd, J=16.6, 8.1 Hz, 1H), 6.49 (d,J=21.7 Hz, 1H), 6.04 (s, 1H), 3.93-3.32 (m, 9H), 2.30 (dd, J=15.5, 8.1Hz, 6H), 1.71 (dd, J=78.7, 6.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ165.79, 165.71, 150.11, 149.72, 138.16, 137.99, 136.85, 136.78, 133.65,133.54, 131.78, 129.71, 129.68, 129.56, 129.46, 129.24, 129.16, 129.13,129.11, 128.75, 128.48, 126.47, 126.41, 123.31, 112.69, 112.49, 111.83,111.64, 67.01, 66.97, 66.69, 56.77, 56.72, 53.57, 53.48, 46.34, 43.07,43.05, 34.73, 34.70, 21.23, 21.15, 21.11, 21.08, 17.00, 16.33. HRMS(ESI-TOF) calculated for C30H34N4O2 [M+H]+ 483.2754, found: 483.2754.

(2S)-1-(3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-129). Reaction of(2S)-1-(3-(hydroxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (71%). ¹HNMR (400 MHz, CDCl₃) δ 7.57-7.40 (m, 1H), 7.28-6.60 (m, 13H), 6.42-6.03(m, 2H), 4.87-4.49 (m, 1H), 4.14-3.31 (m, 9H), 2.71 (d, J=68.1 Hz, 1H),2.33-2.18 (m, 6H), 1.73 (dt, J=112.1, 7.4 Hz, 3H), 1.32-1.12 (m, 2H).¹³C NMR (101 MHz, CDCl₃) δ 166.66, 166.64, 166.55, 149.78, 149.60,149.54, 149.35, 138.30, 138.21, 138.04, 137.87, 136.98, 136.93, 136.86,136.78, 133.64, 133.44, 133.15, 131.67, 131.54, 131.38, 131.20, 129.71,129.66, 129.45, 129.40, 129.26, 129.25, 129.15, 129.12, 129.00, 128.64,128.46, 128.35, 128.22, 128.07, 127.95, 126.68, 126.46, 126.38, 123.96,123.92, 123.70, 123.64, 123.60, 123.50, 112.83, 112.62, 112.59, 112.29,62.64, 62.59, 62.52, 57.88, 57.72, 57.16, 56.94, 54.29, 54.12, 53.98,53.95, 53.61, 53.59, 50.78, 50.73, 50.68, 33.89, 33.86, 33.59, 33.53,31.59, 31.46, 31.36, 22.72, 22.64, 22.57, 21.24, 21.12, 21.10, 21.09,17.32, 17.27, 16.46, 16.44. HRMS (ESI-TOF) calculated for C30H34N4O2[M+H]+ 483.2754, found: 483.2761.

3-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-1-(1-(p-tolyl)ethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-imine(WZ-II-149). Reaction ofN2-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(1-(p-tolyl)ethyl)pyridine-2,3-diaminewith cyanogen bromide yielded the product as brown solid (75%). ¹H NMR(400 MHz, CDCl₃) δ 8.07 (d, J=4.3 Hz, 1H), 7.10-6.98 (m, 6H), 6.94 (d,J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 5.0 Hz, 1H), 6.79-6.75 (m, 1H), 6.64(br, 1H), 5.62 (br, 1H), 4.18 (br, 1H), 3.89 (dd, J=10.7, 3.0 Hz, 1H),3.52 (s, 3H), 3.37 (dd, J=19.3, 9.1 Hz, 1H), 3.27 (dd, J=13.7, 6.9 Hz,1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.87 (d, J=6.9 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 150.92, 143.66, 142.37, 138.13, 136.48, 133.61, 132.60,129.48, 129.13, 129.05, 126.83, 121.95, 119.10, 118.43, 71.71, 59.52,54.42, 33.36, 21.10, 21.04, 17.29. HRMS (ESI-TOF) calculated forC26H30N4O [M+H]+ 415.2498, found: 415.2503. [α]_(D) ²⁰−194 (c 1.502,CHCl₃).

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one(WZ-II-150). Reaction of(S)-2-((2-((4-methylbenzyl)amino)phenyl)amino)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-onewith cyanogen bromide yielded the product as off white solid (88%). ¹HNMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.6 Hz, 1H), 7.31-7.18 (m, 2H), 7.07(dd, J=17.8, 7.7 Hz, 3H), 6.96 (d, J=7.9 Hz, 2H), 6.86 (dd, J=7.5, 5.7Hz, 4H), 6.32 (t, J=8.1 Hz, 1H), 5.79 (d, J=16.7 Hz, 1H), 5.19 (d,J=16.7 Hz, 1H), 5.07 (d, J=9.5 Hz, 1H), 4.82 (d, J=7.0 Hz, 1H), 4.72 (d,J=7.1 Hz, 1H), 4.69 (d, J=7.1 Hz, 1H), 4.62 (d, J=7.0 Hz, 1H), 4.25 (d,J=10.9 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.11 (d, J=10.9 Hz, 1H), 3.42(d, J=8.2 Hz, 2H), 2.29 (s, 3H), 2.23 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 166.53, 150.09, 137.97, 136.75, 131.33, 130.11, 129.95, 129.56,129.44, 129.23, 128.50, 126.98, 124.19, 124.07, 112.92, 110.49, 80.76,80.10, 60.31, 58.53, 57.12, 47.09, 38.24, 33.96, 21.21, 21.16. HRMS(ESI-TOF) calculated for C30H32N4O2 [M+H]+ 481.2604, found: 481.2609.[α]_(D) ²⁰−169 (c 1.260, CHCl₃).

(2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one(WZ-II-151). Reaction of(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (78%). ¹HNMR (400 MHz, CDCl₃) δ 7.53 (dd, J=11.5, 8.3 Hz, 1H), 7.19 (t, J=7.8 Hz,1H), 7.15-6.97 (m, 6H), 6.92 (dd, J=17.9, 8.0 Hz, 2H), 6.75 (d, J=8.0Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.47-6.30 (m, 1H), 6.24 (dd, J=12.1,6.6 Hz, 1H), 5.17 (d, J=7.8 Hz, 1H), 4.88 (dd, J=6.9, 4.0 Hz, 1H),4.80-4.60 (m, 3H), 4.34-4.12 (m, 3H), 3.55-3.32 (m, 2H), 2.36-2.24 (m,6H), 1.89-1.46 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.81, 166.75,150.12, 149.77, 138.26, 137.94, 136.97, 136.88, 133.49, 133.42, 131.35,131.26, 129.66, 129.58, 129.45, 129.42, 129.25, 129.18, 129.04, 128.87,128.59, 128.28, 126.62, 126.42, 123.61, 123.58, 123.54, 123.51, 112.89,112.84, 112.45, 112.19, 80.83, 80.80, 80.28, 80.20, 60.35, 58.62, 58.57,57.16, 56.96, 54.02, 53.91, 38.37, 38.36, 33.80, 33.76, 21.27, 21.15,21.12, 21.09, 17.23, 16.41. HRMS (ESI-TOF) calculated for C31H34N4O2[M+H]+ 495.2760, found: 495.2750.

(2S)-1-(4-hydroxypiperidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-174). Reaction of(2S)-1-(4-hydroxypiperidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (94%). ¹HNMR (400 MHz, CDCl₃) δ 7.61 (ddd, J=11.9, 7.7, 3.8 Hz, 1H), 7.17 (t,J=7.8 Hz, 1H), 7.13-6.94 (m, 5H), 6.91 (d, J=2.8 Hz, 2H), 6.76 (d, J=6.1Hz, 1H), 6.70-6.48 (m, 2H), 6.15 (dd, J=24.0, 17.4 Hz, 1H), 3.97-3.69(m, 3H), 3.63-3.27 (m, 4H), 2.27 (t, J=18.2 Hz, 6H), 2.00-1.51 (m, 5H),1.41-0.77 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.12, 165.06, 164.89,149.59, 149.18, 138.16, 138.11, 137.92, 136.87, 136.71, 133.54, 133.39,131.74, 131.70, 131.59, 131.57, 129.82, 129.64, 129.60, 129.40, 129.17,129.13, 128.92, 128.89, 128.29, 128.01, 127.92, 126.64, 126.55, 126.44,126.42, 123.69, 112.80, 112.56, 112.37, 66.21, 65.74, 65.41, 57.17,57.12, 57.04, 56.98, 54.07, 53.88, 43.16, 43.08, 42.97, 42.69, 40.02,39.87, 34.78, 34.45, 34.36, 34.18, 33.80, 33.40, 33.35, 33.22, 29.69,21.25, 21.13, 21.12, 21.08, 17.49, 17.38, 16.46, 16.32. HRMS (ESI-TOF)calculated for C31H36N4O2 [M+H]+ 497.2917, found: 497.2924.

2-hydroxy-N-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propyl)acetamide(WZ-II-186). Reaction of2-hydroxy-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamidewith cyanogen bromide yielded the product as brown solid (18%). ¹H NMR(400 MHz, CDCl₃) δ 8.24 (s, 1H), 7.21-6.60 (m, 9H), 5.51 (d, J=6.7 Hz,1H), 4.92 (s, 1H), 4.54 (s, 1H), 4.11-3.97 (m, 2H), 3.80 (d, J=14.4 Hz,1H), 3.65 (d, J=11.5 Hz, 1H), 3.27 (dd, J=13.9, 4.8 Hz, 1H), 2.30 (s,6H), 2.23 (s, 3H), 1.55 (d, J=6.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ173.70, 150.70, 138.85, 136.62, 132.98, 129.91, 129.27, 128.50, 126.61,122.44, 118.73, 61.90, 40.75, 34.95, 29.70, 21.07, 20.98, 16.35, 1.02.HRMS (ESI-TOF) calculated for C27H31N5O2 [M+H]+ 458.2566, found:458.2562.

2-hydroxy-N-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propyl)acetamide(WZ-II-187). Reaction of2-hydroxy-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamidewith cyanogen bromide yielded the product as brown solid (18%). ¹H NMR(400 MHz, CDCl₃) δ 8.26 (d, J=4.1 Hz, 1H), 7.41 (s, 1H), 7.22-6.89 (m,6H), 6.74 (dd, J=43.0, 7.6 Hz, 3H), 5.46 (d, J=6.6 Hz, 1H), 5.02 (s,1H), 4.53 (s, 1H), 4.14-3.87 (m, 3H), 3.72 (dd, J=25.2, 12.7 Hz, 2H),3.61-3.43 (m, 1H), 3.26 (dd, J=13.8, 4.3 Hz, 2H), 2.37-2.18 (m, 6H),1.86 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 174.06, 150.20,143.26, 143.00, 138.45, 136.64, 133.17, 132.89, 129.66, 129.37, 126.22,121.90, 120.14, 119.14, 61.64, 60.05, 54.28, 40.51, 35.15, 29.71, 24.78,21.11, 21.09, 16.99. HRMS (ESI-TOF) calculated for C27H31N5O2 [M+H]+458.2566, found: 458.2561.

2-hydroxy-N-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propyl)-N-methylacetamide(WZ-II-205). Reaction of2-hydroxy-N-methyl-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamidewith cyanogen bromide yielded the product as brown oil (10%). HRMS(ESI-TOF) calculated for C28H33N5O2 [M+H]+ 472.2713, found: 472.2711.

2-hydroxy-N-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propyl)-N-methylacetamide(WZ-II-206). Reaction of2-hydroxy-N-methyl-N-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propyl)acetamidewith cyanogen bromide yielded the product as brown oil (10%). HRMS(ESI-TOF) calculated for C28H33N5O2 [M+H]+ 472.2713, found: 472.2707.

(2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(3-(methoxymethyl)azetidin-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-207). Reaction of(2S)-1-(3-(methoxymethyl)azetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (59%). ¹HNMR (400 MHz, CDCl₃) δ 7.32-7.02 (m, 8H), 6.86-6.54 (m, 3H), 6.39 (dd,J=16.0, 7.8 Hz, 1H), 4.36 (dd, J=36.9, 5.8 Hz, 1H), 4.15-3.78 (m, 4H),3.74-3.38 (m, 2H), 3.34-2.83 (m, 7H), 2.64-2.42 (m, 1H), 2.32 (dt,J=33.8, 16.8 Hz, 6H), 1.48-1.15 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ173.20, 173.05, 172.94, 142.63, 142.61, 142.23, 142.21, 139.48, 139.34,138.74, 138.68, 136.40, 136.39, 136.33, 136.32, 136.25, 136.22, 134.78,134.57, 134.19, 134.16, 134.02, 133.91, 129.50, 129.47, 129.37, 129.34,129.25, 129.24, 129.21, 129.20, 125.77, 125.71, 125.69, 122.57, 122.41,121.92, 121.81, 118.55, 118.35, 117.95, 117.80, 117.76, 117.15, 116.98,113.03, 112.99, 112.60, 112.50, 74.30, 74.20, 74.18, 74.16, 59.01,58.96, 58.95, 56.82, 56.77, 56.40, 56.39, 53.15, 52.95, 52.91, 52.68,52.61, 52.50, 50.09, 50.03, 49.98, 49.94, 39.46, 39.35, 39.22, 39.05,28.42, 28.35, 28.09, 28.04, 25.19, 25.14, 25.07, 25.04, 21.12, 21.08.HRMS (ESI-TOF) calculated for C31H36N4O2 [M+H]+ 497.2917, found:497.2910.

(2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one(WZ-II-208-1). Reaction of(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (24%). ¹HNMR (400 MHz, CDCl₃) δ 7.98 (d, J=4.8 Hz, 1H), 7.15 (q, J=8.3 Hz, 4H),7.05 (d, J=7.9 Hz, 2H), 6.97 (d, J=7.8 Hz, 2H), 6.82 (dd, J=7.9, 5.1 Hz,1H), 6.71 (d, J=7.7 Hz, 1H), 6.59 (s, 1H), 5.77 (dd, J=8.1 Hz, 1H), 4.70(dd, J=7.0, 3.6 Hz, 2H), 4.64 (d, J=7.1 Hz, 1H), 4.60 (d, J=7.0 Hz, 1H),4.34 (d, J=9.3 Hz, 1H), 4.17 (ddd, J=20.5, 10.3, 10.3 Hz, 3H), 3.51 (dd,J=13.7, 7.8 Hz, 1H), 3.37 (dd, J=13.6, 9.1 Hz, 1H), 2.34 (s, 3H), 2.24(s, 3H), 1.80 (d, J=6.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.59,151.19, 143.45, 141.52, 138.09, 136.98, 134.02, 131.65, 129.53, 129.20,126.89, 122.48, 118.22, 80.54, 80.21, 60.40, 57.86, 53.56, 37.65, 33.91,21.12, 21.05, 16.83. HRMS (ESI-TOF) calculated for C30H33N5O2 [M+H]+496.2713, found: 496.2707.

(2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)propan-1-one(WZ-II-209-1). Reaction of(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (26%). ¹HNMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.12 (d,J=8.1 Hz, 2H), 7.05 (d, J=7.9 Hz, 2H), 6.99 (d, J=7.6 Hz, 2H), 6.75 (d,J=22.9 Hz, 2H), 5.64 (s, 1H), 4.70 (dd, J=10.3, 7.2 Hz, 2H), 4.63 (d,J=7.1 Hz, 1H), 4.55 (d, J=6.9 Hz, 1H), 4.22-4.09 (m, 3H), 3.99 (d, J=9.1Hz, 1H), 3.54 (dd, J=13.6, 8.1 Hz, 1H), 3.31 (dd, J=20.6, 12.2 Hz, 1H),2.32 (s, 3H), 2.25 (s, 3H), 1.86 (d, J=6.9 Hz, 3H). HRMS (ESI-TOF)calculated for C30H33N5O2 [M+H]+ 496.2713, found: 496.2705.

(2S)-1-(3-(bromomethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propan-1-one(WZ-II-208-2). Reaction of(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (9%). ¹HNMR (400 MHz, CDCl₃) δ 8.23-7.94 (m, 1H), 7.23-6.63 (m, 9H), 6.51 (s,1H), 6.03-5.76 (m, 1H), 4.35-3.23 (m, 10H), 2.37-2.14 (m, 6H), 1.91-1.73(m, 3H). HRMS (ESI-TOF) calculated for C30H34BrN5O2 [M+H]+ 576.1974,found: 576.1974.

(2S)-1-(3-(bromomethyl)-3-(hydroxymethyl)azetidin-1-yl)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propan-1-one(WZ-II-209-2). Reaction of(2S)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (8%). ¹HNMR (400 MHz, CDCl₃) δ 8.04 (dd, J=36.0, 4.5 Hz, 1H), 7.19-6.62 (m, 9H),6.53-6.22 (m, 1H), 5.94 (dd, J=30.9, 22.9 Hz, 1H), 4.35 (d, J=21.0 Hz,1H), 4.23-4.08 (m, 1H), 3.99 (dd, J=22.4, 10.5 Hz, 1H), 3.84-3.63 (m,4H), 3.57-3.30 (m, 4H), 2.38-2.17 (m, 6H), 1.94-1.76 (m, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 167.92, 167.42, 151.03, 150.90, 143.28, 142.36,138.21, 138.16, 137.19, 136.78, 133.89, 133.61, 131.92, 131.74, 129.57,129.38, 129.22, 129.17, 126.78, 122.10, 118.53, 63.86, 63.46, 56.46,56.42, 54.26, 54.17, 53.87, 40.46, 40.25, 36.48, 36.37, 34.09, 33.73,21.11, 21.10, 21.04, 17.24, 17.09. HRMS (ESI-TOF) calculated forC30H34BrN5O2 [M+H]+ 576.1974, found: 576.1976.

(2S)-1-(3-hydroxyazetidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-229). Reaction of(2S)-1-(3-hydroxyazetidin-1-yl)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propan-1-onewith cyanogen bromide yielded the product as off white solid (74%). ¹HNMR (400 MHz, CDCl₃) δ 7.55-7.38 (m, 3H), 7.22-6.60 (m, 11H), 6.26-5.90(m, 2H), 5.02-4.83 (m, 1H), 4.71-4.58 (m, 1H), 4.50 (dd, J=10.8, 4.3 Hz,1H), 4.34-3.83 (m, 4H), 3.49-3.31 (m, 2H), 2.34-2.17 (m, 6H), 1.95-1.51(m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.92, 166.84, 166.50, 166.38,149.61, 149.36, 138.37, 138.30, 138.08, 138.03, 136.94, 136.80, 133.45,133.40, 133.08, 133.04, 131.45, 131.40, 131.30, 131.24, 129.75, 129.48,129.39, 129.26, 129.24, 128.16, 127.94, 127.91, 126.70, 126.65, 126.44,126.42, 123.96, 123.94, 123.90, 123.89, 112.81, 112.74, 112.50, 112.44,61.24, 60.94, 60.85, 60.79, 60.70, 58.85, 58.78, 58.48, 58.41, 57.21,57.08, 54.14, 54.00, 53.96, 33.63, 33.55, 33.49, 21.18, 21.11, 21.07,17.35, 17.28, 16.55, 16.44. HRMS (ESI-TOF) calculated for C29H32N4O2[M+H]+ 469.2604, found: 469.2602.

1-((2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile(WZ-J-230). Reaction of1-((2S)-3-(p-tolyl)-2-((2-((1-(p-tolyl)ethyl)amino)phenyl)amino)propanoyl)azetidine-3-carbonitrilewith cyanogen bromide yielded the product as off white solid (64%). ¹HNMR (400 MHz, CDCl₃) δ 7.48 (dd, J=13.2, 7.6 Hz, 1H), 7.25-6.61 (m,11H), 6.55-6.27 (m, 1H), 6.24-6.09 (m, 0.5H), 5.44 (dd, J=14.5, 8.8 Hz,1H), 5.05-4.71 (m, 0.5H), 4.47 (t, J=9.7 Hz, 1H), 4.36-4.28 (m, 0.5H),4.23-4.12 (m, 0.5H), 3.97 (t, J=7.5 Hz, 1H), 3.64-3.36 (m, 3H),2.36-2.25 (m, 6H), 1.91-1.52 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.30,167.18, 166.86, 166.79, 150.19, 150.01, 149.86, 149.61, 138.45, 138.27,138.14, 137.92, 137.20, 137.09, 136.96, 133.55, 133.31, 133.27, 133.12,131.13, 131.04, 131.00, 130.90, 129.83, 129.79, 129.68, 129.56, 129.50,129.41, 129.34, 129.29, 129.26, 129.22, 129.11, 128.90, 128.85, 128.66,128.56, 128.39, 128.29, 126.70, 126.52, 126.49, 126.38, 124.12, 124.11,124.00, 123.97, 123.63, 123.44, 118.96, 118.94, 113.24, 113.18, 112.72,112.60, 112.51, 112.30, 112.22, 112.15, 57.84, 57.62, 57.14, 56.80,54.69, 54.67, 54.35, 54.21, 54.17, 54.08, 53.99, 53.98, 52.18, 52.11,33.84, 33.77, 33.54, 33.51, 21.26, 21.17, 21.10, 17.70, 17.63, 17.28,17.18, 16.48, 16.34. HRMS (ESI-TOF) calculated for C30H31N5O [M+H]+478.2607, found: 478.2651.

3-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-1-(1-(p-tolyl)ethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-imine(WZ-II-231). Reaction ofN2-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(1-(p-tolyl)ethyl)pyridine-2,3-diaminewith cyanogen bromide yielded the product as brown solid (76%). ¹H NMR(400 MHz, CDCl₃) δ 8.07 (d, J=4.3 Hz, 1H), 7.10-6.98 (m, 6H), 6.94 (d,J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 5.0 Hz, 1H), 6.79-6.75 (m, 1H), 6.64(br, 1H), 5.62 (br, 1H), 4.18 (br, 1H), 3.89 (dd, J=10.7, 3.0 Hz, 1H),3.52 (s, 3H), 3.37 (dd, J=19.3, 9.1 Hz, 1H), 3.27 (dd, J=13.7, 6.9 Hz,1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.87 (d, J=6.9 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 150.92, 143.66, 142.37, 138.13, 136.48, 133.61, 132.60,129.48, 129.13, 129.05, 126.83, 121.95, 119.10, 118.43, 71.71, 59.52,54.42, 33.36, 21.10, 21.04, 17.29. HRMS (ESI-TOF) calculated forC26H30N4O [M+H]+ 415.2498, found: 415.2525.

1-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile(WZ-II-252). Reaction of1-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propanoyl)azetidine-3-carbonitrilewith cyanogen bromide yielded the product as brown solid (58%). ¹H NMR(400 MHz, CDCl₃) δ 8.19-7.90 (m, 1H), 7.21-6.61 (m, 10H), 6.47-6.21 (m,1H), 5.85 (s, 1H), 5.61 (dd, J=14.3, 7.1 Hz, 0.5H), 4.93 (dd, J=5.2, 2.6Hz, 0.5H), 4.71-4.56 (m, 1H), 4.51-4.06 (m, 3H), 3.92 (dt, J=16.4, 8.0Hz, 1H), 3.56 (dqd, J=21.1, 14.2, 6.2 Hz, 3H), 2.28 (dd, J=31.0, 6.8 Hz,6H), 1.78 (dd, J=39.9, 6.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 188.04,167.76, 151.13, 142.46, 138.09, 138.04, 137.00, 136.38, 134.35, 134.22,130.83, 129.54, 129.51, 129.42, 129.25, 129.14, 129.04, 128.86, 126.65,126.60, 126.43, 118.83, 118.18, 118.16, 117.13, 63.91, 54.46, 54.10,53.70, 53.45, 52.25, 50.58, 34.82, 33.53, 21.14, 21.10, 21.06, 17.51,17.44, 17.35, 17.09. HRMS (ESI-TOF) calculated for C29H30N6O [M+H]+479.2554, found: 479.2625. [α]_(D) ²⁰+40 (c 1.070, CHCl₃).

1-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propanoyl)azetidine-3-carbonitrile(WZ-II-253). Reaction of1-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propanoyl)azetidine-3-carbonitrilewith cyanogen bromide yielded the product as brown solid (64%). ¹H NMR(400 MHz, CDCl₃) δ 8.20-8.00 (m, 1H), 7.17-6.73 (m, 10H), 6.57 (ddd,J=31.8, 20.5, 11.4 Hz, 2H), 6.34-5.96 (m, 2H), 4.92 (ddd, J=29.6, 17.0,8.4 Hz, 1H), 4.74-4.56 (m, 1H), 4.45 (t, J=12.4 Hz, 1H), 4.31-4.14 (m,1H), 3.89-3.38 (m, 4H), 2.34-2.19 (m, 6H), 1.81 (dd, J=28.6, 6.6 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.49, 167.46, 150.64, 150.48, 143.18,142.95, 142.80, 138.03, 137.14, 136.94, 133.07, 132.88, 131.47, 131.28,129.58, 129.39, 129.30, 129.13, 128.96, 126.96, 126.79, 126.74, 126.68,121.61, 119.73, 119.23, 119.07, 118.97, 118.78, 55.25, 54.73, 54.57,54.23, 52.60, 52.19, 33.63, 33.52, 21.11, 21.06, 17.50, 17.43. HRMS(ESI-TOF) calculated for C29H30N6O [M+H]+ 479.2554, found: 479.2579.[α]_(D) ²⁰−84 (c 0.917, CHCl₃).

(2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propan-1-ol(WZ-II-269). Reaction of cyanogen bromide with(2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-olyielded the product as brown oil (55%). ¹H NMR (400 MHz, CDCl₃) δ7.35-7.25 (m, 3H), 7.15 (dd, J=11.1, 7.9 Hz, 4H), 7.05 (d, J=7.8 Hz,2H), 6.68 (d, J=6.3 Hz, 1H), 6.35 (t, J=7.1 Hz, 1H), 6.23 (d, J=8.0 Hz,1H), 4.78-4.68 (m, 1H), 4.46-4.33 (m, 2H), 4.21 (dd, J=11.8, 7.0 Hz,1H), 3.28 (dd, J=13.9, 3.5 Hz, 1H), 3.02 (dd, J=14.1, 8.2 Hz, 1H), 2.32(s, 3H), 2.25 (s, 3H), 1.75 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 147.78, 140.19, 136.95, 136.89, 131.69, 131.27, 129.52, 129.48,129.40, 125.93, 118.93, 114.74, 56.37, 55.23, 54.35, 39.71, 24.61,21.12, 21.01. HRMS (ESI-TOF) calculated for C25H28N4O [M+H]+ 401.2336,found: 401.2332. [α]_(D) ²⁰−14 (c 1.025, CHCl₃).

(2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propan-1-ol(WZ-II-270). Reaction of cyanogen bromide with(2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propan-1-olyielded the product as brown oil (48%). ¹H NMR (400 MHz, CDCl₃) δ 7.28(dd, J=10.5, 7.0 Hz, 3H), 7.12 (dd, J=19.1, 7.9 Hz, 8H), 6.74 (d, J=6.3Hz, 1H), 6.42-6.36 (m, 1H), 6.27 (d, J=7.9 Hz, 1H), 4.70 (td, J=10.8,4.0 Hz, 1H), 4.43-4.32 (m, 2H), 4.22 (dd, J=11.9, 7.4 Hz, 1H), 3.37 (dd,J=14.0, 3.8 Hz, 1H), 2.95 (dd, J=13.9, 9.0 Hz, 1H), 2.30 (d, J=8.7 Hz,6H), 1.75 (d, J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 147.76, 140.14,137.02, 136.88, 131.80, 131.52, 129.61, 129.50, 129.34, 125.88, 119.10,114.93, 114.87, 56.65, 55.35, 54.43, 39.81, 24.64, 21.09, 21.04. HRMS(ESI-TOF) calculated for C25H28N4O [M+H]+ 401.2336, found: 401.2328.[α]_(D) ²⁰+112 (c 1.155, CHCl₃).

3-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propoxy)propanenitrile(WZ-III-10). Reaction of cyanogen bromide with3-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propoxy)propanenitrileyielded the product as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d,J=4.8 Hz, 1H), 7.20-7.04 (m, 6H), 6.95 (d, J=7.8 Hz, 2H), 6.88 (dd,J=8.0, 5.1 Hz, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.43-6.35 (m, 1H), 5.79 (s,1H), 4.60 (s, 1H), 4.11-4.00 (m, 1H), 3.96 (dd, J=10.7, 4.2 Hz, 1H),3.73 (dt, J=9.5, 6.4 Hz, 1H), 3.53 (dd, J=13.8, 10.5 Hz, 1H), 3.33 (dd,J=13.8, 6.1 Hz, 1H), 2.70-2.47 (m, 2H), 2.30 (s, 3H), 2.23 (s, 3H), 1.67(d, J=5.8 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 151.23, 143.86, 142.30,138.24, 136.42, 133.48, 132.73, 129.63, 129.36, 129.13, 126.77, 122.22,118.82, 118.27, 117.86, 69.69, 65.93, 54.12, 33.65, 29.69, 21.08, 21.03,18.94, 16.88. HRMS (ESI-TOF) calculated for C28H31N5O [M+H]+ 454.2601,found: 454.2605. [α]_(D) ²⁰+23 (c 0.918, CHCl₃).

3-((2S)-2-(2-imino-1-(1-(p-tolyl)ethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-3-(p-tolyl)propoxy)propanenitrile(WZ-III-11). Reaction of cyanogen bromide with3-((2S)-3-(p-tolyl)-2-((3-((1-(p-tolyl)ethyl)amino)pyridin-2-yl)amino)propoxy)propanenitrileyielded the product as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (dd,J=4.9, 1.0 Hz, 1H), 7.07 (dd, J=14.4, 8.0 Hz, 4H), 6.99-6.90 (m, 3H),6.82 (dd, J=8.1, 1.0 Hz, 3H), 6.43 (d, J=6.5 Hz, 1H), 6.03-5.92 (m, 1H),4.69 (dd, J=10.0 Hz, 1H), 4.13 (ddd, J=10.3, 8.4, 5.2 Hz, 1H), 4.00 (dd,J=10.9, 4.5 Hz, 1H), 3.78 (ddd, J=9.5, 7.1, 5.9 Hz, 1H), 3.56 (dd,J=13.5, 11.2 Hz, 1H), 3.32 (dd, J=13.8, 5.5 Hz, 1H), 2.70-2.55 (m, 2H),2.31 (s, 3H), 2.29 (s, 3H), 1.87 (d, J=6.9 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 150.92, 143.52, 142.69, 138.04, 136.33, 133.49, 132.73, 129.46,129.27, 129.16, 126.56, 121.94, 119.59, 118.53, 117.85, 69.45, 65.97,54.49, 33.62, 29.69, 21.17, 21.10, 19.00, 17.26. HRMS (ESI-TOF)calculated for C28H31N5O [M+H]+ 454.2601, found: 454.2610. [α]_(D)²⁰−145 (c 1.590, CHCl₃).

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propylazetidine-3-carboxylate (WZ-II-2). At room temperature, a solution ofHCl in dioxanes (4M) was added to (S)-1-(tert-butyl)3-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)azetidine-1,3-dicarboxylate. The mixture was stirred for 1 hour. Afterremoving solvent, the residue was purified by flash chromatography using5%-20% MeOH in dichloromethane as eluent. Giving product as off whitesolid (87%). HRMS (ESI-TOF) calculated for C29H32N4O2 [M+H]+ 469.2598,found: 469.2641. [α]_(D) ²⁰−161 (c 1.170, CHCl₃).

(2S)-1-(3-(aminomethyl)-3-(bromomethyl)azetidin-1-yl)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-one(WZ-II-184-1). At room temperature, a solution of HCl in dioxanes (4M)was added to tert-butyl6-((2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.The mixture was stirred for 1 hour. After removing solvent, the residuewas purified by flash chromatography using 5%-20% MeOH indichloromethane as eluent. Giving product as off white solid (10%). ¹HNMR (400 MHz, CDCl₃) δ 7.61-6.58 (m, 11H), 6.05-5.55 (m, 2H), 4.84-3.07(m, 11H), 2.41-2.07 (m, 6H), 1.92-1.50 (m, 3H). HRMS (ESI-TOF)calculated for C31H36BrN5O [M+H]+ 574.2181, found: 574.2184.

(2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)-3-(p-tolyl)propan-1-one(WZ-II-184-2). At room temperature, a solution of HCl in dioxanes (4M)was added to tert-butyl6-((2S)-2-(2-imino-3-(1-(p-tolyl)ethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propanoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.The mixture was stirred for 1 hour. After removing solvent, the residuewas purified by flash chromatography using 5%-20% MeOH indichloromethane as eluent. Giving product as off white solid (65%). ¹HNMR (400 MHz, CDCl₃) δ 9.57-8.81 (m, 2H), 8.62 (s, 1H), 7.47-6.56 (m,8H), 5.82 (d, J=31.4 Hz, 1H), 4.82 (s, 1H), 4.45-3.22 (m, 11H),2.35-2.07 (m, 6H), 1.84-1.48 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.70,166.64, 149.70, 149.41, 138.37, 138.06, 137.14, 136.97, 133.36, 133.15,131.34, 131.18, 129.74, 129.42, 129.29, 129.27, 129.03, 128.88, 127.94,127.81, 126.61, 126.49, 123.97, 112.82, 112.59, 60.77, 60.60, 58.37,58.27, 56.97, 56.80, 55.41, 55.31, 54.40, 53.64, 35.61, 33.41, 29.70,21.09, 21.02, 20.99, 20.86, 16.50, 16.11. HRMS (ESI-TOF) calculated forC31H35N5O [M+H]+ 494.2920, found: 494.2919.

1-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-3-(1-(p-tolyl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(WZ-II-264). At room temperature, to a solution ofN2-((S)-1-methoxy-3-(p-tolyl)propan-2-yl)-N3-(1-(p-tolyl)ethyl)pyridine-2,3-diamine(78 mg, 0.2 mmol, 1 eq.) was added triethylamine (0.069 ml, 0.5 mmol,2.5 eq.), followed by the addition of triphosgene (24 mg, 0.08 mmol, 0.4eq.). The reaction was stirred at room temperature for 1 hour. Saturatedsodium bicarbonate aqueous solution was added to quench the reaction andthe aqueous phase was extracted with ethyl acetate for three times. Thecombined organic phase was concentrated and purified by column using 20%ethyl acetate in hexanes as eluent. Giving product as light yellow oil(86%). ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=5.0 Hz, 1H), 7.11 (s, 4H),6.98 (dd, J=20.5, 7.8 Hz, 4H), 6.73-6.62 (m, 2H), 5.74 (q, J=7.1 Hz,1H), 5.15-5.05 (m, 1H), 4.26 (t, J=9.4 Hz, 1H), 3.81 (dd, J=9.9, 5.5 Hz,1H), 3.48 (dd, J=13.8, 10.3 Hz, 1H), 3.36 (s, 3H), 3.20 (dd, J=13.8, 6.1Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 1.70 (d, J=7.2 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 153.46, 143.92, 139.81, 137.25, 136.21, 135.70,134.59, 129.28, 128.92, 128.87, 126.58, 121.86, 116.12, 115.06, 71.96,58.82, 53.91, 49.90, 34.43, 21.06, 21.03, 17.12. HRMS (ESI-TOF)calculated for C27H30N2O2 [M+H]+ 416.2333, found: 416.2344.

(S)-1-(1-methoxy-3-phenylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-iminn(ARN-163). Reaction of(S)—N1-(1-methoxy-3-phenylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine with cyanogen bromide yielded product asViscous oil (78%); ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.05 (m, 7H),7.00-6.90 (m, 4H), 6.73 (d, J=7.3 Hz, 1H), 5.72 (s, 1H), 5.14-4.84 (m,2H), 4.11-3.93 (m, 1H), 3.85 (dd, J=10.1, 4.6 Hz, 1H), 3.39 (s, 4H),3.27 (dd, J=14.0, 6.2 Hz, 1H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ138.18, 136.11, 129.88, 129.50, 129.17, 128.91, 128.70, 128.53, 126.84,126.27, 125.03, 124.46, 124.35, 73.29, 59.99, 59.41, 47.84, 34.62,21.11.

(1S,2S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-methoxy-1-phenylpropan-1-ol(ARN-212): (1S,2S)-3-methoxy-2-(2-(4-methylbenzylamino)phenylamino)-1-phenylpropan-1-ol with cyanogen bromide yielded productas Viscous oil (80%). [α]_(D) ²⁰+53.8 (c 3.80, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.41-7.33 (m, 2H), 7.20-7.04 (m, 6H), 6.93-6.74 (m, 5H), 6.65(dd, J=7.6, 1.2 Hz, 1H), 5.33 (d, J=4.0 Hz, 1H), 4.97-4.83 (m, 2H), 4.65(td, J=11.1, 9.9, 5.6 Hz, 1H), 4.26 (dd, J=10.2, 8.1 Hz, 1H), 4.15 (dd,J=10.2, 5.0 Hz, 1H), 3.34 (s, 3H), 2.33 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 154.44, 142.23, 137.59, 131.61, 131.01, 129.58, 127.94, 126.84,126.32, 125.38, 121.50, 120.89, 107.11, 73.46, 70.08, 61.48, 59.25,44.78, 21.12. HRMS (ESI-TOF) calcd for C25H28N3O2 [M+H]⁺ 402.2182,found: 402.2205.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-((6-methylpyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-223): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-((6-methylpyridin-2-yl)methyl)benzene-1,2-diamine with cyanogen bromide yieldedproduct as Viscous oil (80%) yield; [α]_(D) ²⁰−213 (c 1.095, CHCl₃); ¹HNMR (400 MHz, CDCl₃) δ 7.38 (t, J=7.7 Hz, 1H), 7.19-6.80 (m, 8H), 6.71(dd, J=7.7, 1.3 Hz, 1H), 6.58-6.35 (m, 1H), 5.10-4.94 (m, 2H), 4.84 (s,1H), 3.97 (q, J=7.4, 6.4 Hz, 2H), 3.78 (dd, J=9.9, 4.9 Hz, 1H), 3.36 (s,4H), 3.22 (dd, J=13.9, 6.5 Hz, 1H), 2.55 (s, 3H), 2.26 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ (158.20, 155.29, 137.14, 135.81, 134.69, 131.46,129.03, 128.97, 122.01, 120.54, 120.24, 117.36, 106.58, 72.32, 59.04,46.90, 34.26, 24.38, 21.09. HRMS (ESI-TOF) calcd for C25H29N4O [M+H]⁺401.2341, found: 401.2364.

(S)-1-(benzo[d]thiazol-2-ylmethyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-237):(S)—N1-(benzo[d]thiazol-2-ylmethyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.26 g, 0.64 mmole) with cyanogen bromide yielded product as Viscousoil (65%); [α]_(D) ²⁰−0.3 (c 7.20, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ8.01 (dt, J=8.3, 0.9 Hz, 1H), 7.80-7.74 (m, 1H), 7.46 (ddd, J=8.3, 7.2,1.2 Hz, 1H), 7.35 (ddd, J=8.2, 7.2, 1.2 Hz, 1H), 7.11-6.84 (m, 8H),5.48-5.27 (m, 2H), 4.60 (d, J=47.6 Hz, 1H), 3.94 (dd, J=10.0, 6.7 Hz,1H), 3.79 (dd, J=10.0, 4.7 Hz, 1H), 3.37 (s, 3H), 3.27 (qd, J=13.9, 7.7Hz, 2H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 167.52, 152.98,136.00, 135.46, 134.53, 130.89, 129.23, 128.90, 126.11, 125.25, 123.06,121.66, 121.00, 120.56, 106.77, 72.18, 59.09, 56.38, 43.95, 34.28,21.10. HRMS (ESI-TOF) calcd for C26H27N4OS [M+H]⁺ 443.1900, found:443.1896.

(S)-1-(3,4-dimethylbenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-238):(S)—N1-(3,4-dimethylbenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.24 g, 0.64 mmole) with cyanogen bromide yielded product as Viscousoil (71%) yield; [α]_(D) ²⁰−72.0 (c 4.35, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.15-6.99 (m, 5H), 7.02-6.86 (m, 4H), 6.82 (s, 2H), 6.78-6.68(m, 1H), 4.95-4.80 (m, 3H), 3.99 (s, 1H), 3.80 (dd, J=9.9, 4.9 Hz, 1H),3.37 (s, 4H), 3.26 (dd, J=13.8, 6.8 Hz, 1H), 2.28 (d, J=3.4 Hz, 9H). ¹³CNMR (100 MHz, CDCl₃) δ 138.34, 136.05, 135.85, 134.93, 131.89, 129.23,129.12, 128.93, 124.48, 120.28, 120.09, 106.52, 77.34, 72.22, 59.02,45.12, 34.34, 21.35, 21.07. HRMS (ESI-TOF) calcd for C27H32N3O [M+H]⁺414.2545, found: 414.2561.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-((2-methylpyrimidin-5-yl)methyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-243):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-((2-methylpyrimidin-5-yl)methyl)benzene-1,2-diamine(0.15 g, 0.48 mmole) with cyanogen bromide yielded product as Viscousoil (60%) yield; [α]_(D) ²⁰=−90.6 (c 2.6, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 8.45 (s, 2H), 7.19-6.79 (m, 7H), 6.79-6.54 (m, 1H), 5.10-4.84(m, 2H), 4.55 (s, 1H), 3.89 (dd, J=10.0, 6.8 Hz, 1H), 3.75 (dd, J=9.9,4.6 Hz, 1H), 3.34 (s, 3H), 3.21 (dd, J=7.9, 3.2 Hz, 2H), 2.69 (s, 3H),2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 167.44, 156.04, 136.35, 134.24,130.88, 129.40, 129.21, 128.81, 128.72, 126.60, 120.72, 120.54, 106.22,72.17, 59.06, 56.42, 40.28, 34.27, 25.71, 21.03. HRMS (ESI-TOF) calcdfor C24H28N5O [M+H]+ 402.2294, found: 402.2314.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(thiophen-3-ylmethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-255):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(thiophen-3-ylmethyl)benzene-1,2-diamine(0.08 g, 0.22 mmole) with cyanogen bromide yielded product as Viscousoil (50%); [α]_(D) ²⁰=−103.6 (c 1.08, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.34-7.19 (m, 1H), 6.95 (dq, J=32.9, 7.3, 6.4 Hz, 8H), 6.85-6.68 (m,2H), 5.02-4.88 (m, 2H), 4.07 (s, 1H), 3.95 (d, J=8.1 Hz, 1H), 3.79 (dd,J=10.1, 4.9 Hz, 1H), 3.37 (s, 4H), 3.21 (dd, J=13.9, 6.3 Hz, 1H), 2.27(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 136.72, 135.92, 134.60, 131.37,129.09, 128.93, 126.43, 121.82, 120.39, 120.23, 106.47, 72.41, 59.05,55.80, 40.83, 34.23, 21.09. HRMS (ESI-TOF) calcd for C23H26N3OS [M+H]⁺392.1791, found: 392.1804.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-256,568,574): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine (0.15 g, 0.40 mmole) with cyanogen bromideyielded product as Viscous oil (80%); [α]_(D) ²⁰=−108.1 (c 4.25, CHCl₃);¹H NMR (400 MHz, CDCl₃) δ 7.19-6.99 (m, 8H), 6.92 (dt, J=23.9, 7.6 Hz,3H), 6.70 (dd, J=7.7, 1.2 Hz, 1H), 4.91 (q, J=16.6 Hz, 3H), 4.69-4.51(m, 1H), 4.07-3.93 (m, 1H), 3.82 (dd, J=9.9, 5.0 Hz, 1H), 3.39 (s, 4H),3.26 (dd, J=13.8, 6.5 Hz, 1H), 2.33 (s, 3H), 2.33 (s, 3H). NMR(100 MHz,CDCl₃) δ 137.06, 135.82, 134.84, 133.05, 131.74, 129.41, 129.10, 129.00,126.68, 120.28, 120.10, 106.49, 72.39, 59.05, 56.17, 44.67, 34.31,21.16, 21.15. HRMS (ESI-TOF) calcd for C26H30N3O [M+H]⁺ 400.2384, found:400.2394.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(quinolin-8-ylmethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-260):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(quinolin-8-ylmethyl)benzene-1,2-diamine(0.11 g, 0.27 mmole) with cyanogen bromide yielded product as Viscousoil (80%); [α]_(D) ²⁰=−108.7 (c 3.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ8.98 (dd, J=4.3, 1.8 Hz, 1H), 8.19-8.09 (m, 1H), 7.72 (d, J=8.1 Hz, 1H),7.47-7.44 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.14-6.73 (m, 9H), 5.73-5.58(m, 2H), 4.90 (s, 1H), 4.03 (s, 1H), 3.83 (dd, J=10.0, 5.0 Hz, 1H), 3.39(s, 4H), 3.26 (dd, J=13.9, 6.5 Hz, 1H), 2.28 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 149.60, 146.08, 136.34, 135.72, 134.88, 133.56, 131.92, 129.06,129.03, 128.25, 127.33, 126.81, 126.36, 121.33, 120.37, 120.11, 106.54,77.40, 72.48, 59.05, 41.15, 34.31, 21.15. HRMS (ESI-TOF) calcd forC₂₈H₂₉N₄O [M+H]⁺ 437.2341, found: 437.2359.

(S)-1-((6-chloropyridin-3-yl)methyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-265):(S)—N1-((6-chloropyridin-3-yl)methyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.11 g, 0.28 mmole) with cyanogen bromide yielded product as Viscousoil (78%); [α]_(D) ²⁰=−100.9 (c 1.2, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ8.26 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H),6.87-6.95 (m, 7H), 6.73-6.58 (m, 1H), 5.06-4.82 (m, 2H), 4.62 (s, 1H),3.98-3.88 (m, 2H), 3.77 (dd, J=9.9, 4.8 Hz, 1H), 3.36 (s, 3H), 3.23 (qd,J=13.9, 7.9 Hz, 2H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.61,148.41, 137.66, 136.15, 134.36, 131.16, 130.95, 129.15, 128.81, 124.29,120.71, 120.50, 106.30, 72.27, 59.09, 56.24, 41.77, 34.25, 21.08. HRMS(ESI-TOF) calcd for C₂₄H₂₆ClN4O [M+H]⁺ 421.1789, found: 421.1793.

(S)-1-((5-chlorobenzo[d]thiazol-2-yl)methyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-269):(S)—N1-((5-chlorobenzo[d]thiazol-2-yl)methyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.10 g, 0.22 mmole) with cyanogen bromide yielded product as Viscousoil (75%); [α]_(D) ²⁰=−95.7 (c 1.15, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=2.0 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.34 (dd, J=8.5, 2.0 Hz,1H), 7.15-6.79 (m, 8H), 5.46-5.24 (m, 2H), 4.60 (s, 1H), 3.92 (dd,J=9.9, 6.7 Hz, 1H), 3.78 (dd, J=10.0, 4.7 Hz, 1H), 3.37 (s, 3H), 3.25(dd, J=7.9, 3.5 Hz, 2H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ169.70, 153.84, 136.04, 134.47, 133.72, 132.15, 130.79, 129.22, 128.86,125.76, 122.93, 122.34, 121.02, 120.58, 106.67, 72.14, 59.09, 56.41,43.88, 34.28, 21.08. HRMS (ESI-TOF) calcd for C26H26ClN4OS [M+H]⁺477.1510, found: 477.1507.

(S)-1-((5-bromobenzo[d]thiazol-2-yl)methyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-279):(S)—N1-((5-bromobenzo[d]thiazol-2-yl)methyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.30 g, 0.62 mmole) with cyanogen bromide yielded product as Viscousoil (78%); [α]_(D) ²⁰=−88.2 (c 1.15, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ8.15 (d, J=1.8 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.45 (dd, J=8.5, 1.9 Hz,1H), 7.11-6.71 (m, 8H), 5.55-5.27 (m, 2H), 4.61 (s, 1H), 4.31 (s, 1H),3.92 (dd, J=10.0, 6.8 Hz, 1H), 3.78 (dd, J=10.0, 4.6 Hz, 1H), 3.36 (s,3H), 3.26 (dd, J=7.8, 4.5 Hz, 2H), 2.26 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 169.48, 154.16, 136.04, 134.47, 134.28, 130.79, 129.23, 128.87,128.37, 125.98, 122.68, 121.05, 120.61, 119.70, 106.70, 72.15, 59.10,56.42, 43.85, 34.28, 21.10. HRMS (ESI-TOF) calcd for C26H26BrN4OS [M+H]⁺521.1011, found: 521.1022.

(S)-1-((5-fluorobenzo[d]thiazol-2-yl)methyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-iminee(ARN-284):(S)—N1-((5-fluorobenzo[d]thiazol-2-yl)methyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.22 g, 0.51 mmole) with cyanogen bromide yielded product as Viscousoil (83%); [α]_(D) ²⁰=−85.6 (c 3.2, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.80-7.62 (m, 2H), 7.21-6.78 (m, 9H), 5.48-5.28 (m, 2H), 4.61 (s, 1H),3.93 (dd, J=10.0, 6.7 Hz, 2H), 3.78 (dd, J=10.0, 4.7 Hz, 1H), 3.37 (s,3H), 3.26 (dd, J=7.9, 4.5 Hz, 2H), 2.26 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 170.22, 162.92, 160.49, 153.84, 136.04, 134.47, 130.82, 129.22,128.87, 122.37, 122.27, 121.04, 120.59, 114.13, 113.88, 109.39, 109.15,106.71, 72.14, 59.08, 56.41, 43.93, 34.28, 21.08. HRMS (ESI-TOF) calcdfor C26H26FN4OS [M+H]⁺ 461.1806, found: 461.1804.

(S)-1-((3-(2-chlorophenyl)isoxazol-5-yl)methyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-288): (S)—N1-((3-(2-chlorophenyl)isoxazol-5-yl)methyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.20 g,0.43 mmole) with cyanogen bromide yielded product as Viscous oil (75%);[α]_(D) ²⁰=−59.0 (c 3.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.62 (m,1H), 7.50-7.43 (m, 1H), 7.38-7.30 (m, 2H), 7.12-6.83 (m, 8H), 6.43 (s,1H), 5.14 (d, J=6.3 Hz, 2H), 4.59 (s, 1H), 3.91 (dd, J=9.9, 6.8 Hz, 1H),3.76 (dd, J=10.0, 4.7 Hz, 1H), 3.35 (s, 3H), 3.94-3.74 (m, 2H), 2.12 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 167.01, 161.22, 136.11, 134.44, 132.88,131.00, 130.91, 130.83, 130.33, 129.15, 128.79, 128.11, 127.05, 120.89,120.60, 106.62, 103.97, 72.16, 59.05, 56.36, 37.43, 34.23, 20.84. HRMS(ESI-TOF) calcd for C28H28ClN4O2 [M+H]⁺ 487.1895, found: 487.1895.

(S)-1-(4-chlorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-303): (S)—N1-(4-chlorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.13 g, 0.34 mmole) with cyanogen bromide yieldedproduct as Viscous oil (80%); [α]_(D) ²⁰=−98.2 (c 3.45, CHCl₃); ¹H NMR(400 MHz, CDCl₃) δ 7.32-7.19 (m, 2H), 7.17-6.81 (m, 9H), 6.64 (dd,J=7.7, 1.2 Hz, 1H), 5.01-4.82 (m, 2H), 4.65-4.46 (m, 1H), 4.04-3.90 (m,1H), 3.80 (dd, J=9.9, 4.9 Hz, 1H), 3.37 (s, 4H), 3.22 (dd, J=13.9, 6.3Hz, 1H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 135.93, 134.72,134.62, 133.16, 131.41, 129.10, 128.93, 128.84, 128.12, 120.47, 120.24,106.41, 72.36, 59.06, 55.93, 44.21, 34.26, 21.12. HRMS (ESI-TOF) calcdfor C25H27ClN3O [M+H]⁺ 420.1837, found: 420.1839.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(3,4,5-trifluorobenzyl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-306):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(3,4,5-trifluorobenzyl)benzene-1,2-diamine(0.11 g, 0.28 mmole) with cyanogen bromide yielded product as Viscousoil (76%); [α]_(D) ²⁰=−103.4 (c 3.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.17-6.86 (m, 7H), 6.74 (p, J=6.3, 5.1 Hz, 2H), 6.67-6.57 (m, 1H),5.03-4.76 (m, 2H), 4.64 (s, 1H), 3.96 (dd, J=10.0, 6.9 Hz, 1H), 3.80(dd, J=9.9, 4.9 Hz, 1H), 3.38 (s, 4H), 3.20 (dd, J=13.9, 6.0 Hz, 1H),2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.42, 152.68, 150.05, 140.20,137.70, 136.31, 134.34, 131.04, 129.22, 128.73, 120.74, 120.45, 110.85,110.79, 110.70, 110.64, 106.27, 72.31, 59.07, 56.27, 43.80, 34.21,20.93. HRMS (ESI-TOF) calcd for C25H25F3N3O [M+H]⁺ 440.1950, found:440.1964.

(S)-1-(3,4-difluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-307):(S)—N1-(3,4-difluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.17 g, 0.45 mmole) with cyanogen bromide yielded product as Viscousoil (71%); [α]_(D) ²⁰=−100.5 (c 4.9, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.18-6.98 (m, 6H), 6.99-6.80 (m, 4H), 6.72-6.58 (m, 1H), 5.02-4.80 (m,2H), 4.71 (s, 1H), 4.02-3.89 (m, 1H), 3.80 (dd, J=9.9, 4.9 Hz, 1H), 3.38(s, 4H), 3.21 (dd, J=13.9, 6.2 Hz, 1H), 2.27 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 151.80, 150.81, 149.33, 148.35, 136.12, 134.49, 133.36, 131.25,129.16, 129.10, 128.82, 122.74, 122.71, 122.68, 122.64, 120.58, 120.33,117.52, 117.34, 115.83, 115.65, 106.34, 72.33, 59.06, 56.10, 43.90,34.23, 21.01. HRMS (ESI-TOF) calcd for C25H26F2N3O [M+H]⁺ 422.2044,found: 422.2048.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-311): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (0.18 g, 0.42 mmole) with cyanogenbromide yielded product as Viscous oil (89%); [α]_(D) ²⁰=−100.5 (c 4.9,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=8.0 Hz, 2H), 7.29-6.78 (m,9H), 6.75-6.52 (m, 1H), 5.14-4.89 (m, 2H), 4.76 (s, 1H), 3.97 (dd,J=10.1, 6.5 Hz, 1H), 3.81 (dd, J=9.9, 4.9 Hz, 1H), 3.38 (s, 4H), 3.23(dd, J=13.9, 6.3 Hz, 1H), 2.29 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ140.31, 135.99, 134.51, 131.33, 129.12, 128.91, 126.92, 125.70, 125.66,125.62, 125.59, 120.58, 120.33, 106.35, 72.39, 59.07, 55.98, 44.35,34.25, 21.04. HRMS (ESI-TOF) calcd for C26H27F3N3O [M+H]⁺ 454.2106,found: 454.2110.

(S)-1-(4-chloro-3-fluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-312):(S)—N1-(4-chloro-3-fluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.19 g, 0.46 mmole) with cyanogen bromide yielded product as Viscousoil (87%); [α]_(D) ²⁰=−103.1 (c 6.9, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.29 (t, J=7.8 Hz, 1H), 7.20-6.78 (m, 9H), 6.63 (dd, J=7.8, 1.3 Hz, 1H),5.04-4.79 (m, 2H), 4.71 (s, 1H), 4.09-3.87 (m, 1H), 3.80 (dd, J=9.9, 4.9Hz, 1H), 3.38 (s, 4H), 3.21 (dd, J=13.9, 6.1 Hz, 1H), 2.28 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 159.48, 157.00, 137.41, 134.48, 131.22, 130.80,129.18, 128.83, 123.15, 120.63, 120.37, 115.08, 114.87, 106.35, 72.34,59.07, 56.12, 43.95, 34.23, 21.04. HRMS (ESI-TOF) calcd for C25H26ClFN3O[M+H]⁺ 438.1748, found: 438.1750.

(S)-1-(3,4-dichlorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-313):(S)—N1-(3,4-dichlorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.08 g, 0.18 mmole) with cyanogen bromide yielded product as Viscousoil (74%); [α]_(D) ²⁰=−100.5 (c 1.55, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.41-7.21 (m, 2H), 7.18-6.80 (m, 8H), 6.74-6.53 (m, 1H), 5.05-4.81 (m,2H), 4.69 (s, 1H), 4.39 (s, 1H), 4.03-3.87 (m, 1H), 3.79 (dd, J=9.9, 4.7Hz, 1H), 3.37 (s, 4H), 3.21 (dd, J=13.9, 6.3 Hz, 1H), 2.27 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 136.63, 136.08, 134.47, 132.80, 131.51, 131.20,130.68, 129.18, 128.82, 128.73, 126.17, 120.71, 120.46, 106.45, 72.26,59.08, 56.21, 43.98, 34.24, 21.08. HRMS (ESI-TOF) calcd for C25H26Cl2N3O[M+H]⁺ 454.1453, found: 454.1450.

(S)-4-((2-imino-3-(1-methoxy-3-p-tolylpropan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (ARN-316):(S)-4-((2-(1-methoxy-3-p-tolylpropan-2-ylamino)phenylamino)methyl)benzonitrile (0.15 g, 0.39 mmole) with cyanogenbromide yielded product as Viscous oil (80%); [α]_(D) ²⁰=−118.3 (c 2.05,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J=7.9 Hz, 2H), 7.25-6.77 (m,9H), 6.60 (d, J=7.5 Hz, 1H), 5.17-4.89 (m, 2H), 4.69 (s, 2H), 3.95 (dd,J=9.9, 7.0 Hz, 1H), 3.79 (dd, J=9.9, 4.7 Hz, 1H), 3.37 (s, 4H), 3.22(dd, J=14.0, 6.4 Hz, 1H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ154.51, 141.89, 136.04, 134.45, 132.49, 131.16, 129.12, 128.89, 127.38,120.72, 120.43, 118.68, 111.29, 106.32, 72.32, 59.09, 56.11, 44.47,34.24, 21.13. HRMS (ESI-TOF) calcd for C26H27N4O [M+H]⁺ 411.2185, found:411.2184.

(S)-1-(4-bromo-3-fluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-317):(S)—N1-(4-bromo-3-fluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.11 g, 0.24 mmole) with cyanogen bromide yielded product as Viscousoil (82%); [α]_(D) ²⁰=−101.6 (c 2.00, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.44 (dd, J=8.2, 7.0 Hz, 1H), 7.21-6.71 (m, 9H), 6.69-6.56 (m, 1H),5.05-4.79 (m, 2H), 4.69 (s, 1H), 4.54 (s, 1H), 4.06-3.88 (m, 1H), 3.79(dd, J=9.9, 4.9 Hz, 1H), 3.37 (s, 4H), 3.21 (dd, J=13.9, 6.1 Hz, 1H),2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 160.47, 158.00, 138.32, 136.15,134.45, 133.70, 131.21, 129.17, 128.81, 123.59, 120.63, 120.37, 114.98,114.75, 107.68, 106.35, 72.33, 59.08, 56.14, 43.99, 34.23, 21.04. HRMS(ESI-TOF) calcd for C25H26BrFN3O [M+H]⁺ 482.1243, found: 482.1276.

(S)-2-bromo-4-((2-imino-3-(1-methoxy-3-p-tolylpropan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile (ARN-320):(S)-2-bromo-4-((2-(1-methoxy-3-p-tolylpropan-2-ylamino)phenylamino)methyl)benzonitrile (0.20 g, 0.43 mmole)with cyanogen bromide yielded product as Viscous oil (70%); [α]_(D)²⁰=−121.3 (c 2.55, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J=8.0,6.3 Hz, 1H), 7.22-6.83 (m, 9H), 6.59 (d, J=7.6 Hz, 1H), 5.18-4.85 (m,2H), 4.74-4.49 (m, 1H), 3.95 (dd, J=10.0, 7.1 Hz, 1H), 3.79 (dd, J=9.9,4.8 Hz, 1H), 3.37 (s, 4H), 3.20 (dd, J=13.9, 6.2 Hz, 1H), 2.27 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 164.71, 162.13, 145.42, 136.28, 134.29,133.71, 130.95, 129.20, 128.76, 123.07, 123.04, 120.87, 120.54, 114.73,114.53, 113.82, 106.22, 72.29, 59.10, 56.31, 44.22, 34.21, 21.03.

(S)-1-(3-bromo-4-fluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-321):(S)—N1-(3-bromo-4-fluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.11 g, 0.24) with cyanogen bromide yielded product as Viscous oil(83%); [α]_(D) ²⁰=−84.2 (c 2.95, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.42(dd, J=6.5, 2.0 Hz, 1H), 7.22-6.77 (m, 9H), 6.72-6.59 (m, 1H), 4.91 (q,J=16.6 Hz, 2H), 4.68 (s, 1H), 4.37 (s, 1H), 4.06-3.88 (m, 1H), 3.78 (dd,J=9.9, 4.8 Hz, 1H), 3.37 (s, 4H), 3.22 (dd, J=13.9, 6.5 Hz, 1H), 2.27(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.60, 157.14, 136.03, 134.58,131.80, 131.28, 129.17, 128.84, 127.41, 127.33, 120.59, 120.34, 116.74,116.52, 109.44, 109.23, 106.37, 72.24, 59.07, 56.13, 43.81, 34.28,21.10. HRMS (ESI-TOF) calcd for C25H26BrFN3O [M+H]⁺ 482.1237, found:482.1218.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-(methylthio)benzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-328): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-(methylthio)benzyl)benzene-1,2-diamine (0.13 g, 0.32 mmole) with cyanogen bromideyielded product as Viscous oil (70%); ¹H NMR (400 MHz, CDCl₃) δ7.24-7.15 (m, 2H), 7.15-6.80 (m, 9H), 6.66 (dd, J=7.5, 1.4 Hz, 1H), 4.89(q, J=16.7 Hz, 2H), 4.40 (s, 1H), 3.96 (s, 1H), 3.79 (dd, J=9.9, 4.9 Hz,1H), 3.37 (s, 4H), 3.22 (dd, J=13.9, 6.5 Hz, 1H), 2.45 (s, 3H), 2.29 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.53, 135.84, 134.72, 133.01, 131.56,129.08, 128.98, 128.94, 127.26, 126.96, 120.34, 120.14, 106.46, 72.35,59.05, 55.84, 44.45, 34.27, 21.13, 15.94.

(S)-1-(4-tert-butylbenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-333):(S)—N1-(4-tert-butylbenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.23 g, 0.55 mmole) with cyanogen bromide yieldedproduct as Viscous oil (72%); [α]_(D) ²⁰=−83.8 (c 4.7, CHCl₃); ¹H NMR(400 MHz, CDCl₃) δ 7.42-7.30 (m, 2H), 7.23-6.81 (m, 9H), 6.81-6.65 (m,1H), 5.07-4.81 (m, 2H), 4.70 (s, 1H), 4.01 (s, 1H), 3.83 (dd, J=9.9, 5.0Hz, 1H), 3.40 (s, 4H), 3.26 (dd, J=13.9, 6.5 Hz, 1H), 2.32 (s, 3H), 1.34(s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 154.98, 150.29, 135.77, 134.85,132.98, 131.79, 129.10, 129.01, 126.35, 125.64, 120.28, 120.07, 106.46,72.43, 59.06, 55.72, 44.51, 34.50, 34.31, 31.39, 21.18. HRMS (ESI-TOF)calcd for C₂₉H₃₆N₃O [M+H]⁺ 442.2852, found: 442.2850.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-(trifluoromethoxy)benzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-337): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-(trifluoromethoxy)benzyl)benzene-1,2-diamine (0.17 g, 0.45 mmole) with cyanogenbromide yielded product as Viscous oil (71%); [α]_(D) ²⁰=−91.4 (c 3.55,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.23-6.83 (m, 11H), 6.71-6.61 (m, 1H),5.06-4.86 (m, 2H), 4.77 (s, 1H), 4.39 (s, 1H), 4.04-3.91 (m, 1H), 3.80(dd, J=9.9, 4.9 Hz, 1H), 3.38 (s, 4H), 3.23 (dd, J=13.9, 6.3 Hz, 1H),2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 148.44, 148.42, 135.95, 134.89,134.57, 131.39, 129.09, 128.92, 128.04, 121.19, 120.51, 120.28, 106.38,72.38, 59.05, 55.95, 44.08, 34.25, 21.02. HRMS (ESI-TOF) calcd forC26H27F3N3O2 [M+H]⁺ 470.2050, found: 470.2047.

(S)-3-((2-imino-3-(1-methoxy-3-p-tolylpropan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile(ARN-338): (S)-3-((2-(1-methoxy-3-p-tolylpropan-2-ylamino)phenylamino)methyl)benzonitrile (0.13 g, 0.34) with cyanogen bromideyielded product as Viscous oil (85%); [α]_(D) ²⁰=−105.3 (c 4.0, CHCl₃);¹H NMR (400 MHz, CDCl₃) δ 7.57-7.29 (m, 4H), 7.19-6.84 (m, 7H),6.72-6.55 (m, 1H), 5.12-4.93 (m, 2H), 4.66 (s, 1H), 4.02-3.89 (m, 1H),3.79 (dd, J=9.9, 4.7 Hz, 1H), 3.37 (s, 4H), 3.22 (dd, J=13.9, 6.4 Hz,1H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.45, 138.12, 136.16,134.50, 131.26, 131.22, 131.18, 130.20, 129.53, 129.19, 128.83, 120.72,120.44, 118.65, 112.85, 106.31, 72.22, 59.09, 56.26, 44.18, 34.29,21.08. HRMS (ESI-TOF) calcd for C26H27N4O [M+H]⁺ 411.2185, found:411.2204.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-344): (S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(3-(trifluoromethyl)benzyl)benzene-1,2-diamine tolylpropan (0.29 g, 0.68 mmole) withcyanogen bromide yielded product as Viscous oil (71%); [α]_(D) ²⁰=−85.1(c 7.65, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.4 Hz, 2H), 7.39(d, J=7.8 Hz, 1H), 7.29-7.14 (m, 1H), 7.16-6.81 (m, 7H), 6.66 (dd,J=7.6, 1.2 Hz, 1H), 5.08-4.95 (q, J=16.8 Hz, 2H), 4.73 (s, 1H), 3.99 (t,J=8.3 Hz, 1H), 3.81 (dd, J=9.9, 4.8 Hz, 1H), 3.38 (s, 4H), 3.25 (dd,J=13.9, 6.4 Hz, 1H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.47,136.03, 134.63, 131.40, 130.03, 129.28, 129.15, 128.88, 124.39, 124.36,123.63, 123.59, 120.62, 120.35, 106.39, 72.26, 59.03, 56.16, 44.55,34.30, 21.04. HRMS (ESI-TOF) calcd for C26H27F3N3O [M+H]⁺ 454.2106,found: 454.2122.

(R)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-phenylpropan-1-ol (ARN-350):(R)-2-(2-(4-methylbenzylamino)phenylamino)-3-phenylpropan-1-ol (0.10 g,0.30 mmole) with cyanogen bromide yielded product as Viscous oil (85%);¹H NMR (400 MHz, CDCl₃) δ 7.47-7.04 (m, 8H), 6.91 (dt, J=8.9, 5.5 Hz,2H), 6.76 (dd, J=14.2, 7.1 Hz, 2H), 4.88 (d, J=4.8 Hz, 2H), 4.44-4.19(m, 1H), 4.12 (d, J=12.4 Hz, 1H), 4.00 (dd, J=12.4, 4.6 Hz, 1H), 3.44(dd, J=13.5, 7.5 Hz, 1H), 3.30 (dd, J=13.4, 7.9 Hz, 1H), 2.36 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 154.87, 138.54, 137.71, 132.30, 131.66,131.59, 129.70, 129.44, 128.38, 126.67, 126.41, 121.01, 120.52, 106.92,106.73, 62.95, 59.43, 44.93, 33.82, 21.18. HRMS (ESI-TOF) calcd forC24H26N3O [M+H]⁺ 372.2070, found: 372.2071.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-353) Mixture of Distereomers:(S)—N1-(3,4-difluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.17 g, 0.45) with cyanogen bromide yielded product as Viscous oil(71%); [α]_(D) ²⁰=−100.5 (c 4.9, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.41-7.25 (m, 4H), 7.25-7.12 (m, 1H), 7.01 (s, 4H), 6.95-6.84 (m, 1H),6.75 (t, J=7.8 Hz, 1H), 6.45 (dt, J=7.9, 1.5 Hz, 1H), 5.68 (s, 1H), 4.76(s, 1H), 3.96 (t, J=8.4 Hz, 1H), 3.84 (ddd, J=9.4, 5.2, 3.9 Hz, 2H),3.40 (d, J=1.9 Hz, 4H), 3.22 (ddd, J=13.8, 6.4, 2.7 Hz, 1H), 2.29 (d,J=3.6 Hz, 3H), 1.78 (dd, J=16.3, 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ139.55, 135.90, 134.71, 134.65, 130.09, 129.04, 128.96, 128.59, 128.52,127.30, 127.27, 126.57, 119.84, 108.43, 108.27, 72.49, 59.06, 50.45,50.32, 34.19, 21.08, 16.19. HRMS (ESI-TOF) calcd for C26H30N3O [M+H]⁺400.2389, found: 400.2389.

(S)-1-(3-chloro-4-fluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-362):(S)—N1-(3-chloro-4-fluorobenzyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.15 g, 0.36 mmol) with cyanogenbromide yielded product as Viscous oil (75%); [α]_(D) ²⁰=−100.3 (c 5.5,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.22 (m, 1H), 7.19-6.84 (m, 9H),6.65 (d, J=7.5 Hz, 1H), 5.00-4.80 (m, 2H), 4.74 (s, 1H), 3.98 (t, J=8.8Hz, 1H), 3.80 (dd, J=9.9, 4.8 Hz, 1H), 3.37 (s, 4H), 3.23 (dd, J=13.9,6.3 Hz, 1H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.62, 156.15,136.02, 134.61, 131.30, 129.18, 128.95, 128.86, 126.61, 126.54, 120.59,120.34, 116.87, 116.66, 106.35, 72.27, 59.05, 56.12, 43.84, 34.27,21.09. HRMS (ESI-TOF) calcd for C25H26ClFN3O [M+H]⁺ 438.1743, found:438.1778.

(S)-1-(3,4-difluorobenzyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-366): (S)—N1-(4-methylbenzyl)-N2-(1-(4-methylbenzyloxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.24 g, 0.52 mmole) with cyanogenbromide yielded product as Viscous oil (74%); [α]_(D) ²⁰=−62.7 (c 2.65,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.24-6.87 (m, 15H), 6.72 (dd, J=6.9,1.8 Hz, 1H), 5.05-4.89 (m, 4H), 4.64-4.42 (m, 3H), 4.05 (s, 1H), 3.92(dd, J=10.0, 4.9 Hz, 1H), 3.39 (td, J=14.5, 13.1, 7.1 Hz, 2H), 3.27 (dd,J=13.9, 6.4 Hz, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 137.28, 137.06, 135.83, 134.93, 134.73, 132.90,131.60, 129.41, 129.36, 129.09, 129.05, 128.98, 127.84, 126.69, 120.44,120.31, 106.70, 73.14, 69.83, 44.82, 34.35, 29.76, 21.22, 21.15, 21.14.HRMS (ESI-TOF) calcd for C33H36N3O [M+H]⁺ 490.2852, found: 490.2857.

(R)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol (ARN-374):(R)-2-(2-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol (0.24 g,0.66 mmole) with cyanogen bromide yielded product as white solid (80%)yield; [α]_(D) ²⁰=+126.2 (c 5.86, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.25-7.07 (m, 6H), 7.03 (d, J=7.5 Hz, 2H), 7.00-6.85 (m, 2H), 6.85-6.68(m, 2H), 4.94-4.85 (m, 2H), 4.26 (dt, J=12.2, 6.1 Hz, 1H), 4.07 (d,J=12.4 Hz, 1H), 3.94 (ddd, J=11.9, 4.5, 1.4 Hz, 1H), 3.43 (ddd, J=13.8,8.3, 1.8 Hz, 1H), 3.15 (dd, J=13.4, 7.2 Hz, 1H), 2.35 (d, J=1.7 Hz, 3H),2.28 (d, J=1.7 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.85, 137.75,135.85, 135.35, 132.16, 131.64, 129.69, 129.29, 129.05, 126.60, 121.04,120.49, 106.87, 106.70, 62.65, 59.54, 44.99, 33.33, 21.13, 21.04. HRMS(ESI-TOF) calcd for C25H28N3O+ [M+H]⁺ 386.2226, found: 386.2229.

(R)-1-(4-methylbenzyl)-3-(1-(4-(methylthio)benzyloxy)-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-375): (R)—N1-(4-methylbenzyl)-N2-(1-(4-(methylthio)benzyloxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.24 g, 0.48 mmole)with cyanogen bromide yielded product as Viscous oil (70%); [α]_(D)²⁰=+49.3 (c 2.745, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.24-6.99 (m, 12H),6.98-6.86 (m, 2H), 6.72 (dd, J=7.0, 1.7 Hz, 1H), 4.94 (q, J=16.6 Hz,3H), 4.63-4.45 (m, 3H), 4.07 (s, 1H), 3.94 (dd, J=10.0, 5.0 Hz, 1H),3.41 (s, 1H), 3.29 (dd, J=13.8, 6.4 Hz, 1H), 2.38 (s, 3H), 2.36 (s, 3H),2.33 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.05, 137.28, 137.04, 135.82,135.00, 134.87, 133.06, 131.72, 129.43, 129.11, 129.07, 129.01, 127.84,126.70, 120.29, 120.14, 106.52, 73.14, 69.82, 55.95, 44.72, 34.39,21.25, 21.18, 21.17. HRMS (ESI-TOF) calcd for C33H36N3OS+ [M+H]⁺522.2573, found: 522.2581.

(R)-1-(4-methylbenzyl)-3-(1-(4-methylbenzyloxy)-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-376):(R)—N1-(4-methylbenzyl)-N2-(1-(4-methylbenzyloxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.25 g, 0.54 mmole) with cyanogen bromide yielded product as whitesolid (73%); [α]_(D) ²⁰=+56.0 (c 6.89, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.21-7.10 (m, 4H), 7.11-6.93 (m, 8H), 6.96-6.77 (m, 3H), 6.76-6.63 (m,1H), 4.99-4.80 (m, 3H), 4.59-4.36 (m, 3H), 4.02 (s, 1H), 3.86 (dd,J=9.9, 4.9 Hz, 1H), 3.33 (s, 1H), 3.22 (dd, J=13.8, 6.6 Hz, 1H), 2.47(s, 3H), 2.31 (s, 3H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.65,137.07, 135.85, 134.83, 134.72, 132.93, 131.66, 129.39, 129.07, 128.93,128.27, 126.60, 126.52, 120.25, 120.11, 106.47, 72.73, 69.70, 44.67,34.37, 29.71, 21.11, 21.10, 15.90. HRMS (ESI-TOF) calcd for C33H36N3O+[M+H]⁺ 490.2852, found: 490.2846.

N-(1-(4-methylbenzyl)-3-(1-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)methanamine type (ARN-387): White solid (76%) yield; [α]_(D) ²⁰=+41.8 (c8.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.23 (m, 2H), 7.21-7.03 (m,5H), 6.90-6.74 (m, 2H), 6.73-6.61 (m, 1H), 6.44-6.30 (m, 1H), 5.07-4.79(m, 2H), 4.57 (ddt, J=8.9, 7.7, 5.6 Hz, 1H), 4.32 (dd, J=12.5, 8.8 Hz,1H), 4.06 (dd, J=12.6, 5.8 Hz, 1H), 3.20 (dd, J=13.7, 5.5 Hz, 1H), 2.96(dd, J=13.7, 7.6 Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 161.26, 137.27, 137.12, 136.36, 134.20, 133.20, 130.34, 129.46,129.41, 129.34, 127.45, 120.79, 120.05, 107.83, 106.96, 63.78, 60.22,46.11, 39.19, 21.19, 21.16. HRMS (ESI-TOF) calcd for C25H26N3+ [M+H]⁺368.2121, found: 368.2119.

(S)-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol (ARN-388,525,557):(S)-2-(2-(4-methylbenzylamino)phenylamino)-3-p-tolyl propan-1-ol (0.20g, 0.55) with cyanogen bromide yielded product as Viscous oil (90%);[α]_(D) ²⁰=−113.5 (c 3.45, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.08(m, 6H), 7.03 (d, J=7.5 Hz, 2H), 6.98-6.87 (m, 2H), 6.87-6.69 (m, 2H),4.90 (d, J=4.2 Hz, 2H), 4.26 (dt, J=11.9, 6.0 Hz, 1H), 4.07 (d, J=12.4Hz, 1H), 3.94 (dd, J=12.4, 4.2 Hz, 1H), 3.43 (dd, J=13.2, 8.3 Hz, 1H),3.15 (dd, J=13.4, 7.2 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 154.91, 137.70, 135.85, 135.38, 132.28, 131.65, 129.70,129.32, 129.12, 129.09, 126.65, 121.04, 120.51, 106.96, 106.73, 62.67,59.48, 44.94, 33.40, 21.17, 21.09. HRMS (ESI-TOF) calcd for C₂₅H₂₈N₃O[M+H]⁺ 386.2227, found: 386.2230.

(S)-1-(1-(3-chloro-4-fluorobenzyloxy)-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-392):(S)—N1-(1-(3-chloro-4-fluorobenzyloxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.10 g, 0.20 mmole) with cyanogen bromide yielded product as Viscousoil (71%); [α]_(D) ²⁰=−40.0 (c 0.83, CHCl₃); H NMR (400 MHz, CDCl₃) δ7.23 (dd, J=7.2, 2.0 Hz, 2H), 7.19-6.79 (m, 13H), 6.71 (dd, J=6.7, 2.0Hz, 1H), 5.06-4.74 (m, 3H), 4.59-4.32 (m, 3H), 4.07 (s, 1H), 3.85 (dd,J=9.9, 4.6 Hz, 1H), 3.62 (s, 2H), 3.35 (s, 1H), 3.22 (dd, J=13.9, 6.8Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.65,156.18, 137.17, 135.94, 132.79, 131.62, 129.71, 129.40, 129.11, 128.90,127.24, 127.16, 126.60, 120.36, 120.23, 116.42, 116.21, 106.59, 71.76,69.83, 44.72, 34.39, 30.94, 29.70, 21.09.

(S)-1-(1-ethoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-409):(S)—N1-(1-ethoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.17 g, 0.45) with cyanogen bromide yielded product as Viscous oil(80%) yield; [α]_(D) ²⁰=−81.0 (c 4.7, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.22-6.98 (m, 9H), 6.91 (dt, J=24.0, 7.6 Hz, 2H), 6.69 (d, J=7.6 Hz,1H), 5.02-4.83 (m, 3H), 4.68 (s, 1H), 3.99 (s, 1H), 3.88 (dd, J=10.0,5.0 Hz, 1H), 3.62-3.47 (m, 2H), 3.29 (dd, J=13.8, 6.5 Hz, 1H), 2.34 (s,3H), 2.31 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ δ137.02, 135.77, 134.96, 133.11, 131.73, 129.39, 129.08, 129.00, 126.70,120.21, 120.10, 106.47, 70.33, 66.70, 55.86, 44.66, 34.33, 21.15, 21.14,15.26. HRMS (ESI-TOF) calcd for C27H32N3O+ [M+H]⁺ 414.2540, found:414.2540.

(S)-1-(4-methylbenzyl)-3-(1-propoxy-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-414): (S)—N1-(4-methylbenzyl)-N2-(1-propoxy-3-p-tolylpropan-2-yl)benzene-1,2-diamine (0.17 g, 0.42 mmole) with cyanogen bromide yieldedproduct as Viscous oil (71%); [α]_(D) ²⁰=−79.1 (c 4.8, CHCl₃); ¹H NMR(400 MHz, CDCl₃) δ 7.38-6.79 (m, 11H), 6.70 (d, J=7.5 Hz, 1H), 5.01-4.88(m, 2H), 4.68 (s, 1H), 3.98 (s, 1H), 3.88 (dd, J=10.1, 5.0 Hz, 1H),3.56-3.20 (m, 4H), 2.33 (d, J=12.7 Hz, 6H), 1.62 (h, J=7.1 Hz, 2H), 0.92(t, J=7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.02, 135.77, 135.00,133.12, 131.72, 129.39, 129.09, 129.01, 126.71, 120.20, 120.09, 106.45,73.05, 70.55, 55.97, 44.68, 34.33, 22.97, 21.15, 21.14, 10.68. HRMS(ESI-TOF) calcd for C28H34N3O+ [M+H]⁺ 428.2696, found: 428.2712.

(S)-1-(1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-422):(S)—N1-(1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.17 g, 0.45) with cyanogen bromide yielded product as Viscous oil(68%) yield; [α]_(D) ²⁰=−101.21 (c 6.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃)δ 7.11-6.85 (m, 11H), 6.77-6.63 (m, 1H), 4.96-4.84 (m, 3H), 3.95 (dd,J=10.1, 5.2 Hz, 1H), 3.74-3.56 (m, 2H), 3.52 (t, J=4.7 Hz, 2H), 3.35 (s,4H), 3.26 (dd, J=13.9, 6.3 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 137.03, 135.77, 134.83, 133.04, 131.68, 129.38,129.06, 128.98, 126.67, 120.26, 120.13, 106.48, 71.94, 71.01, 70.58,59.02, 55.88, 44.65, 34.27, 21.14, 21.12. HRMS (ESI-TOF) calcd forC28H34N3O2 [M+H]⁺ 444.2646, found: 444.2650.

(S)-1-(1-(4-isopropylbenzyloxy)-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-424):(S)—N1-(1-(4-isopropylbenzyloxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.10 g, 0.20 mmole) with cyanogen bromide yielded product as Viscousoil (71%); ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.16 (m, 4H), 7.15-6.86 (m,10H), 6.73 (dd, J=7.0, 1.8 Hz, 1H), 5.02-4.85 (m, 3H), 4.64-4.48 (m,2H), 4.35 (s, 1H), 4.08 (s, 1H), 3.95 (dd, J=10.0, 5.1 Hz, 1H), 3.41 (s,1H), 3.30 (dd, J=13.9, 6.4 Hz, 1H), 3.00-2.90 (m, 1H), 2.36 (s, 3H),2.33 (s, 3H), 1.31 (d, J=7.0 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 148.31,137.05, 135.82, 135.40, 134.86, 133.05, 131.72, 129.43, 129.11, 129.01,127.85, 126.70, 126.45, 120.30, 120.17, 106.54, 73.16, 69.88, 44.73,34.41, 33.92, 24.11, 21.17.

1-(2-methoxypropyl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-iminetype mol. (ARN-441): Viscous oil (51%); ¹H NMR (400 MHz, CDCl₃) (7.28(d, J=7.8 Hz, 2H), 7.25-7.11 (m, 4H), 7.03 (d, J=7.8 Hz, 2H), 5.72-5.48(m, 2H), 4.27-3.89 (m, 4H), 3.71-3.57 (m, 1H), 3.38 (s, 3H), 2.20 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.03, 135.77, 134.83, 133.04, 131.68,129.38, 129.06, 128.98, 126.67, 120.26, 120.13, 106.48, 71.94, 71.01,70.58, 59.02, 55.88, 44.65, 34.27, 21.14, 21.12. HRMS (ESI-TOF) calcdfor C₁₉H₂₂N₃O [M+H]⁺ 308.1758, found: 308.1770.

(S)-2-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropoxy)-N,N-dimethylethanamine(ARN-452):(S)—N1-(1-(2-(dimethylamino)ethoxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.40 g, 0.93 mmole) with cyanogen bromide yielded product as Viscousoil (68%); [α]_(D) ²⁰=−80.6 (c 2.06, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.43 (s, 2H), 7.16-6.78 (m, 10H), 5.45-5.05 (m, 6H), 4.09 (dd, J=10.8,6.9 Hz, 1H), 3.91 (dd, J=10.7, 4.0 Hz, 1H), 3.60 (m, J=16.1, 10.6, 5.5Hz, 2H), 3.65-3.54 (m, 2H), 2.57-2.06 (m, 12H). ¹³C NMR (100 MHz, CDCl₃)δ 152.65, 137.30, 136.04, 133.63, 131.73, 130.78, 129.38, 129.13,128.87, 126.81, 121.99, 121.88, 108.63, 70.77, 69.22, 58.51, 57.35,45.75, 45.57, 34.17, 21.09, 21.07. HRMS (ESI-TOF) calcd for C29H37N4O[M+H]⁺ 457.2962, found: 457.2965.

(S)-methyl3-(2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropoxy)propanoate(ARN-460): (S)-methyl 3-(2-(2-(4-methylbenzylamino)phenylamino)-3-p-tolylpropoxy)propanoate (0.17 g, 0.38 mmole) with cyanogenbromide yielded product as Viscous oil (62%); [α]_(D) ²⁰=−73.2 (c 4.5,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.17-6.86 (m, 11H), 6.69 (d, J=7.5 Hz,1H), 5.03-4.47 (m, 5H), 4.02 (s, 1H), 3.89 (dd, J=10.0, 4.9 Hz, 1H),3.83-3.69 (m, 2H), 3.63 (s, 2H), 3.46-3.29 (m, 1H), 3.30-3.15 (m, 1H),2.31 (d, J=14.7 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 171.93, 137.07,135.81, 132.96, 131.63, 129.41, 129.09, 128.99, 128.91, 126.65, 120.35,120.17, 106.51, 70.83, 66.67, 51.67, 44.69, 34.97, 34.91, 34.20, 21.15,21.13. HRMS (ESI-TOF) calcd for C29H34N3O3+ [M+H]⁺ 472.2595, found:472.2605.

(S)-1-(1-(3,5-bis(trifluoromethyl)benzyloxy)-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-485): (S)—N1-(1-(3,5-bis(trifluoromethyl)benzyloxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.31 g, 0.56 mmole) with cyanogen bromide yielded product as Viscousoil (65%) yield; [α]_(D) ²⁰=−34.8 (c 4.9, CHCl₃); H NMR (400 MHz, CDCl₃)δ 7.75 (d, J=36.2 Hz, 3H), 7.21-6.86 (m, 11H), 6.74 (dd, J=7.4, 1.5 Hz,1H), 4.90 (d, J=5.9 Hz, 2H), 4.74-4.53 (m, 2H), 4.23 (s, 2H), 3.95 (dd,J=10.0, 4.6 Hz, 1H), 3.45 (s, 1H), 3.28 (dd, J=13.9, 6.9 Hz, 1H), 2.33(s, 3H), 2.32 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 140.85, 137.22,136.02, 134.58, 132.78, 131.70, 129.43, 129.17, 128.93, 127.37, 127.26,127.22, 126.57, 124.66, 121.95, 121.41, 120.42, 120.26, 106.59, 71.61,71.58, 71.56, 70.46, 44.63, 34.39, 21.07. HRMS (ESI-TOF) calcd forC29H36N3O2+ [M+H]⁺ 458.2802, found: 458.2815.

(S)-1-(1-(3-methoxypropoxy)-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine (ARN-496):(S)—N1-(1-(3-methoxypropoxy)-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.20 g, 0.46 mmole) with cyanogen bromide yielded product as Viscousoil (83%) yield; [α]_(D) ²⁰=−72.1 (c 3.17, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.15-6.85 (m, 11H), 6.69 (d, J=7.5 Hz, 1H), 5.00-4.83 (m, 2H),4.42 (s, 1H), 3.98 (s, 1H), 3.86 (dd, J=10.0, 4.9 Hz, 1H), 3.64-3.46 (m,2H), 3.39 (t, J=6.5 Hz, 3H), 3.27 (s, 4H), 2.32 (s, 3H), 2.32 (s, 3H),1.83 (p, J=6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 137.04, 135.80,134.89, 133.05, 131.67, 129.39, 129.09, 128.98, 126.68, 120.25, 120.13,106.49, 70.60, 69.56, 68.15, 58.60, 58.57, 44.66, 34.31, 29.98, 21.13.HRMS (ESI-TOF) calcd for C29H36N3O2+ [M+H]⁺ 458.2802, found: 458.2815.

(S)-2-(2-imino-7-methyl-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-524):(S)-2-(2-methyl-6-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol(0.35 g, 0.94 mmole) with cyanogen bromide yielded product as Viscousoil (80%) yield; [α]_(D) ²⁰=−106.51 (c 4.5, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.22-7.08 (m, 6H), 7.03 (d, J=7.7 Hz, 2H), 6.83 (t, J=7.7 Hz,1H), 6.68 (d, J=7.8 Hz, 2H), 4.93-4.84 (m, 3H), 4.16 (dd, J=12.3, 1.1Hz, 1H), 3.99 (dd, J=12.3, 4.8 Hz, 1H), 3.48 (dd, J=13.6, 7.8 Hz, 1H),3.35 (dd, J=13.5, 7.5 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 155.45, 137.71, 135.81, 135.57, 132.27,132.13, 129.74, 129.71, 129.29, 129.04, 126.63, 125.43, 120.62, 118.39,105.20, 63.96, 60.15, 44.93, 33.21, 21.17, 21.07, 20.25. HRMS (ESI-TOF)calcd for C26H30N3O [M+H]⁺ 400.2383, found: 400.2382.

(S)-2-(2-imino-3-(4-methylbenzyl)-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-528): (S)-2-(2-(4-methylbenzylamino)-4-(trifluoromethyl)phenylamino)-3-p-tolylpropan-1-ol (0.30 g, 0.70 mmole) withcyanogen bromide yielded product as white solid (71%) yield; [α]_(D)²⁰=−136.0 (c 3.6, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.14 (m, 3H),7.09 (d, J=7.9 Hz, 4H), 7.04-6.94 (m, 3H), 6.73 (d, J=8.3 Hz, 1H),4.98-4.82 (m, 2H), 4.35 (q, J=7.1 Hz, 1H), 4.17-3.96 (m, 2H), 3.38-3.24(m, 2H), 2.36 (s, 3H), 2.26 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.00,138.01, 136.09, 134.93, 134.37, 131.63, 131.54, 129.82, 129.12, 126.54,118.60, 118.55, 106.63, 103.35, 103.32, 62.90, 59.96, 45.02, 33.36,21.12, 20.97. HRMS (ESI-TOF) calcd for C26H27F3N30+ [M+H]⁺ 454.2100,found: 454.2093.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-531):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)-4-(trifluoromethyl)benzene-1,2-diamine(0.25 g, 0.55 mmole) with cyanogen bromide yielded product as Viscousoil (74%) yield; [α]_(D) ²⁰=−103.0 (c 4.35, CHCl₃); H NMR (400 MHz,CDCl₃) δ 7.15 (dd, J=41.0, 7.8 Hz, 3H), 7.06-6.92 (m, 6H), 6.89 (d,J=1.8 Hz, 1H), 4.93 (d, J=8.4 Hz, 2H), 3.98 (s, 1H), 3.77 (dd, J=10.0,4.4 Hz, 1H), 3.37 (s, 4H), 3.20 (dd, J=14.0, 6.3 Hz, 2H), 2.32 (s, 3H),2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 137.50, 136.09, 134.20, 131.95,131.63, 129.56, 129.15, 128.88, 128.84, 126.53, 118.21, 118.16, 103.25,103.21, 72.28, 59.09, 44.93, 34.06, 21.11, 21.07. HRMS (ESI-TOF) calcdfor C27H29F3N3O [M+H]⁺ 468.2257, found: 468.2252.

(S)-2-(7-fluoro-2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-535):(S)-2-(2-fluoro-6-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol(0.30 g, 0.79 mmole) with cyanogen bromide yielded product as Viscousoil (70%) yield; ¹H NMR (400 MHz, CDCl₃) δ 7.33-6.91 (m, 8H), 6.83-6.78(m, 1H), 6.77-6.61 (m, 1H), 6.54 (d, J=7.8 Hz, 1H), 4.89-4.85 (m, 3H),4.19 (d, J=12.5 Hz, 1H), 3.99 (d, J=12.7 Hz, 1H), 3.37 (s, 2H), 2.37 (s,3H), 2.29 (s, 3H). MS (ESI-TOF) calcd for C25H27FN3O [M+H]⁺ 404.2138,found: 404.3000.

(S)-4-fluoro-3-(1-methoxy-3-p-tolylpropan-2-yl)-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-541):(S)-3-fluoro-N2-(1-methoxy-3-p-tolylpropan-2-yl)-N1-(4-methylbenzyl)benzene-1,2-diamine(0.24 g, 0.59 mmole) with cyanogen bromide yielded product as Viscousoil (68%); ¹H NMR (400 MHz, CDCl₃) δ 7.23-6.51 (m, 10H), 6.47 (d, J=7.6Hz, 1H), 5.07-4.87 (m, 2H), 4.76 (d, J=17.2 Hz, 1H), 4.23 (s, 2H), 3.77(s, 1H), 3.37 (s, 3H), 3.16 (dd, J=13.5, 6.3 Hz, 2H), 2.30 (d, J=13.4Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 137.16, 135.80, 134.62, 132.55,129.40, 129.31, 129.06, 128.96, 128.84, 126.58, 108.78, 108.57, 102.97,102.94, 73.79, 58.99, 55.30, 45.06, 36.59, 21.12, 21.10.

(S)-2-(2-imino-5-methyl-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-545):(S)-2-(4-methyl-2-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol(0.15 g, 0.42) with cyanogen bromide yielded product as Viscous oil(80%) yield; [α]_(D) ²⁰=−155.0 (c 2.8, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.30-6.92 (m, 8H), 6.80 (q, J=8.1 Hz, 2H), 6.64 (s, 1H), 5.04-4.77 (m,2H), 4.42 (s, 1H), 4.20-3.94 (m, 2H), 3.43 (dd, J=13.5, 7.5 Hz, 1H),3.20 (dd, J=13.3, 7.8 Hz, 1H), 2.58-2.09 (m, 9H). ¹³C NMR (100 MHz,CDCl₃) δ 154.76, 137.55, 135.79, 135.27, 132.33, 131.69, 130.58, 129.67,129.29, 129.24, 129.11, 126.56, 121.77, 107.79, 107.25, 62.55, 59.58,44.88, 33.45, 21.41, 21.20, 21.19, 21.14. HRMS (ESI-TOF) calcd forC26H30N3O [M+H]⁺ 400.2383, found: 400.2388.

(S)—N-(1-(1-methoxy-3-p-tolylpropan-2-yl)-5-methyl-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-ylidene)methanamine (ARN-547): white solid (68%);[α]_(D) ²⁰=−230.60 (c 1.65, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d,J=8.5 Hz, 1H), 7.42-7.29 (m, 1H), 7.10 (d, J=7.9 Hz, 2H), 7.03-6.85 (m,3H), 6.79 (d, J=7.8 Hz, 2H), 6.70 (d, J=7.7 Hz, 2H), 5.59 (d, J=17.5 Hz,1H), 5.20 (d, J=17.6 Hz, 1H), 4.99 (qd, J=8.0, 4.3 Hz, 1H), 4.26 (dd,J=10.3, 8.3 Hz, 1H), 4.14 (dd, J=10.3, 4.4 Hz, 1H), 3.43 (s, 2H), 3.26(d, J=7.9 Hz, 2H), 2.89 (s, 4H), 2.44 (s, 3H), 2.32 (s, 3H), 2.16 (d,J=9.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.76, 137.55, 135.79,135.27, 132.33, 131.69, 130.58, 129.67, 129.29, 129.24, 129.11, 126.56,121.77, 107.79, 107.25, 62.55, 59.58, 44.88, 33.45, 21.41, 21.20, 21.19,21.14. HRMS (ESI-TOF) calcd for C28H33N3O [M+H]⁺ 428.2696, found:428.2699.

(S)—N-(1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-ylidene)methanamineStructure not confirmed(ARN-567): Viscous oil (67%); [α]_(D) ²⁰=−318.0(c 13.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=8.3 Hz, 1H),7.43-7.28 (m, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.83(d, J=7.9 Hz, 2H), 6.67-6.42 (m, 6H), 5.42 (d, J=17.5 Hz, 1H), 5.09-4.92(m, 1H), 4.87 (ddt, J=12.8, 8.8, 4.5 Hz, 1H), 4.12 (dd, J=10.5, 8.8 Hz,1H), 3.96 (dd, J=10.5, 4.0 Hz, 1H), 3.18 (s, 3H), 3.07 (qd, J=14.1, 7.9Hz, 2H), 2.70 (s, 5H), 2.05 (s, 3H), 1.90 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 154.25, 137.66, 136.36, 132.67, 130.95, 130.10, 129.49, 129.09,128.42, 128.22, 125.91, 125.34, 114.85, 112.14, 71.68, 62.39, 59.26,49.61, 42.60, 34.02, 20.96, 20.92.

(S)-2-(2-imino-3-(4-methylbenzyl)-6-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-572): (S)-2-(2-(4-methylbenzylamino)-5-(trifluoromethyl)phenylamino)-3-p-tolylpropan-1-ol (0.30 g, 0.70 mmole) withcyanogen bromide yielded product as white (80%); [α]_(D) ²⁰=−156.50 (c6.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.27-6.88 (m, 9H), 6.75 (d, J=7.5Hz, 2H), 4.99-4.82 (m, 2H), 4.33 (s, 1H), 4.21-4.00 (m, 2H), 3.41-3.19(m, 2H), 2.37 (s, 3H), 2.23 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.89,138.02, 137.99, 136.17, 135.04, 133.88, 131.95, 131.69, 129.79, 129.09,129.07, 126.62, 117.84, 106.03, 104.09, 63.26, 60.12, 44.99, 33.57,21.13, 20.87. HRMS (ESI-TOF) calcd for C26H27F3N3O [M+H]⁺ 454.2106,454.2103.

(S)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1-(4-methylbenzyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-575): Viscous oil (68%); [α]_(D) ²⁰=−101.21 (c 6.3, CHCl₃); ¹H NMR(400 MHz, CDCl₃) δ 7.21-6.88 (m, 10H), 6.68 (d, J=8.1 Hz, 1H), 4.98-4.88(m, 3H), 4.62 (s, 1H), 4.00 (s, 1H), 3.79 (dd, J=10.0, 4.4 Hz, 1H), 3.39(s, 4H), 3.22 (dd, J=13.9, 6.3 Hz, 1H), 2.33 (s, 3H), 2.27 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 154.79, 137.44, 136.09, 134.29, 134.15, 132.25,129.51, 129.12, 128.91, 126.61, 122.68, 117.83, 117.78, 105.79, 72.33,59.04, 56.43, 44.83, 34.16, 21.11, 21.04. HRMS (ESI-TOF) calcd forC27H29F3N3O [M+H]⁺ 468.2257, found: 468.2250.

(S)-3-(1-methoxy-3-p-tolylpropan-2-yl)-5-methyl-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-586):(S)—N2-(1-methoxy-3-p-tolylpropan-2-yl)-4-methyl-N1-(4-methylbenzyl)benzene-1,2-diamine(0.20 g, 0.50 mmole) with cyanogen bromide yielded product as Viscousoil (83%); ¹H NMR (400 MHz, CDCl₃) δ 7.24-6.80 (m, 9H), 6.70 (d, J=8.0Hz, 1H), 6.58 (d, J=7.9 Hz, 1H), 4.94-4.83 (m, 3H), 4.02 (s, 1H), 3.82(dd, J=9.9, 5.1 Hz, 1H), 3.40 (s, 4H), 3.26 (dd, J=13.9, 6.4 Hz, 1H),2.43-2.29 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 155.06, 136.99, 135.80,134.93, 133.15, 129.83, 129.64, 129.38, 129.14, 129.09, 129.04, 126.67,126.63, 120.50, 106.17, 72.29, 59.03, 44.70, 34.36, 29.77, 21.64, 21.14.

(S)-2-(2-imino-3-(4-methylbenzyl)-5-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-589)(S)-2-(2-(4-methylbenzylamino)-4-(trifluoromethyl)phenylamino)-3-p-tolylpropan-1-ol(0.17 g, 0.40 mmole) with cyanogen bromide yielded product as whitesolid (80%); [α]_(D) ²⁰=−121.04 (c 5.05, CHCl₃); ¹H NMR (400 MHz, CDCl₃)δ 7.24-7.14 (m, 3H), 7.10 (dd, J=8.1, 2.7 Hz, 4H), 7.06-6.92 (m, 3H),6.72 (d, J=8.3 Hz, 1H), 4.99-4.83 (m, 2H), 4.33 (td, J=8.1, 4.9 Hz, 1H),4.15-3.97 (m, 2H), 3.30 (qd, J=13.6, 7.7 Hz, 2H), 2.37 (s, 3H), 2.26 (s,3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.01, 138.02, 136.09, 134.98, 134.42,131.66, 131.55, 129.83, 129.14, 129.11, 126.55, 118.58, 118.54, 106.54,103.31, 103.27, 62.94, 59.97, 45.03, 33.35, 21.13, 20.97. HRMS (ESI-TOF)calcd for C26H27F3N3O [M+H]⁺ 454.2101, found: 454.2104.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-592):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)-4-(trifluoromethyl)benzene-1,2-diamine(0.15 g, 0.34 mmole) with cyanogen bromide yielded product as Viscousoil (78%) yield; [α]_(D) ²⁰=−80.0 (c 5.32, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 7.30-6.84 (m, 11H), 5.02-4.81 (m, 3H), 4.75 (s, 1H), 4.02 (s,1H), 3.80 (dd, J=10.0, 4.5 Hz, 1H), 3.39 (s, 4H), 3.23 (dd, J=13.9, 6.3Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.01,137.42, 136.04, 134.43, 132.24, 131.83, 129.57, 129.17, 128.91, 126.56,126.10, 118.03, 117.99, 102.96, 102.92, 72.30, 59.05, 44.74, 34.11,21.11, 21.09.

(S)-2-(2-imino-4-methyl-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-603):(S)-2-(3-methyl-2-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol(0.20 g, 0.53 mmole) with cyanogen bromide yielded product as Viscousoil (68%); [α]_(D) ²⁰=−146.8 (c 5.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.35-6.81 (m, 9H), 6.71 (t, J=6.5 Hz, 2H), 5.16 (q, J=17.9 Hz, 2H), 4.31(s, 1H), 4.17-3.86 (m, 2H), 3.50 (dd, J=13.6, 8.4 Hz, 1H), 3.18 (dd,J=13.1, 7.0 Hz, 1H), 2.55-2.07 (m, 9H). ¹³C NMR (100 MHz, CDCl₃) δ155.38, 137.42, 135.84, 135.45, 133.79, 131.93, 129.80, 129.75, 129.39,129.12, 125.71, 124.22, 121.01, 118.14, 105.18, 62.56, 59.38, 46.35,33.29, 21.16, 21.13, 18.22. HRMS (ESI-TOF) calcd for C26H30N3O [M+H]⁺400.23890, found: 400.23890.

(S)-1-(1-methoxy-3-p-tolylpropan-2-yl)-4-methyl-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-608):(S)—N1-(1-methoxy-3-p-tolylpropan-2-yl)-3-methyl-N2-(4-methylbenzyl)benzene-1,2-diamine(0.20 g, 0.50 mmole) with cyanogen bromide yielded product as Viscousoil (76%); [α]_(D) ²⁰=−109.4 (c 1.84, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.19-6.99 (m, 7H), 6.90-6.84 (m, 3H), 6.65 (d, J=7.6 Hz, 1H), 5.17 (s,2H), 4.39 (s, 1H), 4.02 (s, 1H), 3.82 (dd, J=9.9, 5.1 Hz, 1H), 3.38 (s,4H), 3.23 (dd, J=13.9, 6.4 Hz, 1H), 2.41-2.25 (m, 9H). NMR (100 MHz,CDCl₃) δ 154.57, 136.70, 135.80, 134.89, 134.82, 134.80, 134.67, 129.67,129.48, 129.09, 129.00, 125.61, 123.84, 120.28, 117.85, 72.25, 59.05,55.71, 46.10, 34.21, 21.14, 21.10, 18.41. HRMS (ESI-TOF) calcd forC27H32N3O [M+H]⁺ 414.2545, found: 414.2541.

(S)-2-(5-chloro-2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(ARN-626):(S)-2-(4-chloro-2-(4-methylbenzylamino)phenylamino)-3-p-tolylpropan-1-ol(0.20 g, 0.50 mmole) with cyanogen bromide yielded product as Viscousoil (74%); ¹H NMR (400 MHz, CDCl₃) δ 7.17-6.78 (m, 9H), 6.66 (dd,J=11.3, 5.1 Hz, 2H), 4.87-4.70 (m, 2H), 4.33 (s, 1H), 3.97 (qd, J=12.2,4.2 Hz, 3H), 3.26-3.12 (m, 2H), 2.30 (s, 3H), 2.22 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 155.07, 137.74, 135.95, 134.68, 132.33, 131.65, 129.97,129.65, 129.03, 128.96, 126.43, 125.92, 120.67, 108.08, 107.16, 62.59,59.18, 44.85, 33.31, 21.03, 20.95.

(S)-5-chloro-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-629):(S)-4-chloro-N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.20 g, 0.49 mmole) with cyanogen bromide yielded product as Viscousoil (75%); ¹H NMR (400 MHz, CDCl₃) δ 7.17-6.83 (m, 10H), 6.66 (d, J=2.0Hz, 1H), 4.91-4.78 (m, 2H), 4.64 (s, 2H), 3.98 (s, 1H), 3.78 (dd, J=9.9,4.6 Hz, 1H), 3.38 (s, 4H), 3.19 (dd, J=13.9, 6.2 Hz, 1H), 2.34 (s, 3H),2.30 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.79, 137.29, 135.94, 134.51,132.71, 132.42, 129.51, 129.14, 128.93, 126.59, 125.57, 120.03, 106.81,72.40, 59.07, 56.00, 44.72, 34.12, 21.15.

(S)-5-bromo-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-632):(S)-4-bromo-N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.13 g, 0.30 mmole) with cyanogen bromide yielded product as Viscousoil (68%); [α]_(D) ²⁰=−120.21 (c 0.85, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.16-6.84 (m, 11H), 6.78 (d, J=1.8 Hz, 1H), 4.86 (dd, J=17.1, 14.4 Hz,2H), 4.60 (s, 1H), 3.96 (s, 1H), 3.77 (dd, J=9.9, 4.6 Hz, 1H), 3.37 (s,4H), 3.18 (dd, J=13.9, 6.2 Hz, 1H), 2.34 (s, 3H), 2.30 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 154.74, 137.30, 135.94, 134.51, 133.03, 132.39,129.51, 129.13, 128.91, 126.57, 126.55, 122.87, 119.98, 112.65, 109.39,106.77, 72.37, 59.07, 44.72, 44.69, 34.10, 21.15, 21.14.

(S)-5,6-dichloro-1-(1-methoxy-3-p-tolylpropan-2-yl)-3-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-642):(S)-4,5-dichloro-N1-(1-methoxy-3-p-tolylpropan-2-yl)-N2-(4-methylbenzyl)benzene-1,2-diamine(0.13 g, 0.30 mmole) with cyanogen bromide yielded product as Viscousoil (68%); [α]_(D) ²⁰=−25.3 (c 1.1, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.10 (d, J=7.8 Hz, 2H), 7.04-6.93 (m, 6H), 6.67 (s, 1H), 4.84 (t, J=16.4Hz, 2H), 3.93 (s, 1H), 3.73 (dd, J=10.0, 4.4 Hz, 1H), 3.37 (s, 3H), 3.16(dd, J=13.9, 6.3 Hz, 1H), 2.33 (s, 3H), 2.29 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 137.48, 136.11, 134.20, 131.99, 131.37, 129.55, 129.17, 128.88,126.50, 123.50, 123.41, 107.51, 72.24, 59.07, 53.45, 44.81, 34.01,21.12, 21.10. HRMS (ESI-TOF) calcd for C26H28Cl2N3O [M+H]⁺ 468.1604,found: 468.1611.

(S)-5-bromo-3-(1-methoxy-3-p-tolylpropan-2-yl)-1-(4-methylbenzyl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-643):(S)-4-bromo-N2-(1-methoxy-3-p-tolylpropan-2-yl)-N1-(4-methylbenzyl)benzene-1,2-diamine(0.15 g, 0.36 mmole) with cyanogen bromide yielded product as Viscousoil (71%); [α]_(D) ²⁰=−82.4 (c 4.7, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ7.24-6.87 (m, 11H), 6.49 (d, J=8.2 Hz, 1H), 4.93-4.78 (m, 2H), 4.61 (s,1H), 3.97 (s, 1H), 3.76 (dd, J=10.0, 4.6 Hz, 1H), 3.38 (s, 4H), 3.20(dd, J=13.9, 6.5 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 154.76, 137.26, 135.99, 134.46, 132.52, 130.85, 129.47, 129.40,129.15, 129.09, 128.98, 126.68, 126.60, 122.68, 112.79, 107.35, 72.23,59.06, 55.98, 44.70, 34.16, 21.15. HRMS (ESI-TOF) calcd for C26H29BrN3O[M+H]⁺ 478.1489, found: 478.1491.

(S)-1-(4-methylbenzyl)-3-(1-(methylthiomethoxy)-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-757):(S)—N1-(4-methylbenzyl)-N2-(1-(methylthiomethoxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.17 g, 0.45) with cyanogen bromide yielded product as Viscous oil(68%) yield; [α]_(D) ²⁰=−101.21 (c 6.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃)δ 7.20-6.79 (m, 11H), 6.76-6.60 (m, 1H), 4.95-4.83 (m, 2H), 4.63 (s,2H), 4.18 (s, 2H), 3.92 (dd, J=10.0, 4.9 Hz, 1H), 3.38 (s, 1H), 3.22(dd, J=13.9, 6.4 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 1.96 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 137.10, 135.90, 134.59, 132.92, 131.66, 129.38,129.11, 128.93, 126.63, 120.29, 120.13, 106.48, 75.45, 67.52, 55.51,44.67, 34.49, 21.12, 13.74. HRMS (ESI-TOF) calcd for C27H31N3OS [M+H]⁺446.2260, found: 446.2265.

(S,Z)-2-(2-(methoxymethylimino)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropan-1-ol(Structure was not confirmed)(ARN-795): Viscous oil (80%); [α]_(D)²⁰=−82.4 (c 4.7, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=8.6 Hz,1H), 7.65 (t, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.41 (d, J=8.4 Hz,1H), 7.07 (d, J=7.9 Hz, 2H), 6.96 (d, J=7.7 Hz, 2H), 6.82 (d, J=7.7 Hz,2H), 6.73 (d, J=7.8 Hz, 2H), 5.89 (d, J=16.4 Hz, 1H), 5.72 (tdd, J=9.5,5.9, 3.9 Hz, 1H), 5.52 (d, J=16.4 Hz, 1H), 4.67 (d, J=6.5 Hz, 2H), 4.55(d, J=6.5 Hz, 2H), 4.48-4.30 (m, 2H), 4.22 (dd, J=10.8, 4.1 Hz, 1H),3.41 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ150.14, 138.11, 136.95, 133.04, 130.66, 130.02, 129.58, 129.50, 129.02,128.24, 127.16, 127.12, 125.86, 115.41, 114.49, 96.58, 67.05, 61.92,55.64, 50.37, 49.42, 34.74, 21.09, 21.02.

1-(cyclopropyl(p-tolyl)methyl)-3-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imine(ARN-805):N1-(cyclopropyl(p-tolyl)methyl)-N2-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.05 g, 0.11 mmole) with cyanogen bromide yielded product as Viscousoil (71%); ¹H NMR (400 MHz, CDCl₃) δ 7.25-6.75 (m, 12H), 4.27-3.97 (m,3H), 3.84-3.71 (m, 2H), 3.68-3.18 (m, 8H), 2.34-2.19 (m, 6H), 1.22-0.77(m, 3H), 0.60-0.20 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 137.75, 133.88,132.73, 132.65, 129.41, 129.29, 129.18, 128.96, 128.89, 127.96, 126.93,123.21, 122.99, 71.70, 70.79, 62.68, 58.88, 21.10, 21.08, 21.05, 13.70,6.35, 6.24, 3.53.

1-(cyclopropyl(p-tolyl)methyl)-3-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)-1H-benzo[d]imidazol-2(3H)-imineMixture of DM (ARN-826):N1-(cyclopropyl(p-tolyl)methyl)-N2-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)benzene-1,2-diamine(0.05 g, 0.12 mmole) with cyanogen bromide yielded product as Viscousoil (70%); ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J=30.3, 8.4 Hz, 1H),7.57-7.39 (m, 1H), 7.25-6.78 (m, 10H), 4.81-4.62 (m, 2H), 4.35-4.07 (m,2H), 3.54-3.44 (m, 2H), 3.36-3.11 (m, 3H), 2.43-2.16 (m, 6H), 1.69 (s,1H), 1.11-0.77 (m, 2H), 0.73-0.39 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ154.76, 137.26, 135.99, 134.46, 132.52, 130.85, 129.47, 129.40, 129.15,129.09, 128.98, 126.68, 126.60, 122.68, 112.79, 107.35, 72.23, 59.06,55.98, 44.70, 34.16, 21.15.

2-((2S)-2-(2-imino-3-(1-p-tolylethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropoxy)ethanol(ARN-846): Viscous oil (90%); ¹H NMR (400 MHz, CDCl₃) δ 9.37 (s, 1H),7.97 (dd, J=5.1, 1.4 Hz, 1H), 7.09-6.94 (m, 6H), 6.89-6.73 (m, 3H), 6.67(dt, J=7.8, 2.4 Hz, 2H), 5.62 (s, 1H), 4.26 (s, 1H), 3.84 (ddd, J=22.2,10.6, 3.8 Hz, 2H), 3.63 (ddd, J=10.8, 5.4, 3.4 Hz, 1H), 3.52-3.25 (m,6H), 3.20 (dd, J=14.0, 6.6 Hz, 1H), 2.18 (s, 3H), 2.07 (s, 3H), 1.65 (d,J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 150.77, 143.44, 142.73,138.06, 136.30, 133.33, 132.43, 129.43, 128.99, 128.96, 126.80, 121.60,119.57, 118.73, 71.42, 70.68, 70.23, 59.17, 54.67, 33.24, 21.03, 20.93,17.02.

(2S)-2-(3-(cyclopropyl(p-tolyl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropylacetate (ARN-851): (2S)-2-(2-(cyclopropyl(p-tolyl)methylamino)phenylamino)-3-p-tolylpropyl acetate (0.20 g, 0.45 mmole) with cyanogenbromide yielded product as Viscous oil (74%); ¹H NMR (400 MHz, CDCl₃) δ7.59 (d, J=9.1 Hz, 1H), 7.37-6.72 (m, 11H), 6.21 (s, 1H), 5.75 (dd,J=18.2, 10.0 Hz, 1H), 4.89-4.56 (m, 2H), 3.53-3.24 (m, 2H), 2.25 (d,J=21.4 Hz, 6H), 2.05 (d, J=14.2 Hz, 3H), 1.82-1.53 (m, 1H), 1.17-0.79(m, 2H), 0.56-0.03 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 170.43, 150.95,137.64, 137.41, 136.51, 136.47, 133.88, 131.81, 129.39, 129.24, 129.21,129.10, 129.04, 128.92, 126.85, 126.65, 123.26, 123.24, 122.99, 122.94,113.04, 112.59, 63.79, 63.65, 62.73, 62.59, 57.42, 34.26, 21.17, 21.10,21.07, 20.95, 13.77, 13.59, 6.42, 6.25, 3.30, 2.80. HRMS (ESI-TOF) calcdfor C30H34N3O2 [M+H]⁺ 468.2651, found: 468.2633.

(2S)-2-(3-(cyclopropyl(p-tolyl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropylcyclopropanecarboxylate salt (ARN-855): (2S)-2-(2-(cyclopropyl(p-tolyl)methylamino)phenylamino)-3-p-tolylpropylcyclopropane carboxylate (0.13g, 0.28 mmole) with cyanogen bromide yielded product as Viscous oil(65%); ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 2H), 7.63 (t, J=7.8 Hz, 1H),7.25-6.77 (m, 11H), 6.23 (s, 1H), 5.75 (dd, J=25.0, 9.9 Hz, 1H), 4.83(td, J=12.3, 7.6 Hz, 1H), 4.60 (dd, J=11.4, 4.6 Hz, 2H), 3.36 (dt,J=12.8, 6.0 Hz, 2H), 2.26 (d, J=4.8 Hz, 6H), 1.80-1.51 (m, 2H),1.28-0.70 (m, 7H), 0.52-−0.00 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ174.25, 150.87, 137.60, 137.39, 136.46, 136.41, 133.89, 131.83, 129.36,129.22, 129.17, 129.14, 129.07, 128.98, 128.87, 126.86, 126.71, 126.63,123.27, 123.04, 113.14, 113.03, 112.69, 63.51, 63.37, 62.73, 62.57,57.48, 57.36, 34.18, 34.02, 21.18, 21.10, 21.07, 13.76, 13.61, 13.03,12.93, 8.88, 6.43, 6.27, 3.30, 2.77. HRMS (ESI-TOF) calcd for C32H36N3O2[M+H]⁺ 494.2808, found: 494.2801.

(2S)-2-(3-(cyclopropyl(p-tolyl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropyl1-methylazetidine-3-carboxylate (ARN-857):(2S)-2-(2-(cyclopropyl(p-tolyl)methylamino)phenylamino)-3-p-tolylpropyll-methylazetidine-3-carboxylate(0.15 g, 0.36 mmole) with cyanogen bromide yielded product as Viscousoil (80%); ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=8.2 Hz, 1H), 7.46-6.71(m, 12H), 5.94-5.73 (m, 1H), 5.08-4.84 (m, 1H), 4.82-4.71 (m, 1H),3.90-3.19 (m, 8H), 2.94-2.72 (m, 3H), 2.39-2.12 (m, 6H), 1.76-1.63 (m,1H), 1.03-0.76 (m, 3H), 0.61-0.21 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δMixture of DM: Due to mixture not good 13 C.

(2S)-2-(3-(cyclopropyl(p-tolyl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-p-tolylpropyl1-acetylazetidine-3-carboxylate (ARN-861):(2S)-2-(2-(cyclopropyl(p-tolyl)methylamino)phenylamino)-3-p-tolylpropyll-acetylazetidine-3-carboxylate(0.20 g, 0.38 mmole) with cyanogen bromide yielded product as Viscousoil (74%); ¹H NMR (400 MHz, CDCl₃) δ 9.04 (t, J=9.6 Hz, 2H), 7.52 (d,J=8.3 Hz, 1H), 7.32-6.73 (m, 11H), 6.31-6.09 (m, 1H), 5.80-5.51 (m, 1H),4.87-4.70 (m, 2H), 4.38-3.95 (m, 4H), 3.40 (dd, J=34.0, 7.8 Hz, 3H),2.38-2.17 (m, 6H), 1.82-1.66 (m, 3H), 1.08-0.73 (m, 3H), 0.32-0.17 (m,2H). ¹³C NMR (100 MHz, CDCl₃) δ 171.76, 171.69, 171.65, 170.73, 150.71,137.95, 136.70, 136.67, 136.63, 133.67, 133.63, 133.51, 131.53, 129.51,129.33, 129.29, 129.23, 129.04, 128.93, 128.56, 126.80, 126.73, 126.56,126.47, 123.54, 123.26, 113.38, 113.22, 113.15, 112.16, 62.88, 62.83,57.51, 52.69, 50.30, 50.25, 34.31, 31.51, 31.45, 21.17, 21.09, 21.07,18.74, 18.64, 13.55, 13.41, 6.29, 6.18, 2.77.

(2-((S)-1-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-p-tolylethyl)-4,5-dihydrooxazol-5-yl)methanolMixture of Distereomers (ARN-909) Yield (90%); H NMR (400 MHz, CDCl₃) δ7.22 (d, J=31.6 Hz, 3H), 7.03 (q, J=6.2, 4.7 Hz, 4H), 6.84 (d, J=16.1Hz, 6H), 5.81-5.60 (m, 1H), 5.29-5.07 (m, 2H), 4.66 (dt, J=38.9, 5.1 Hz,2H), 3.70-3.38 (m, 7H), 2.27 (s, 3H), 2.18 (s, 3H). ¹³C NMR (100 MHz,CDCl₃) δ 150.34, 138.27, 136.88, 136.78, 131.37, 129.84, 129.68, 129.30,128.83, 128.73, 126.70, 124.22, 118.29, 115.37, 110.16, 80.07, 79.77,60.46, 60.40, 60.22, 46.20, 39.52, 38.05, 34.41, 21.09, 21.06, 21.00,14.18, 13.52.

3-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)-1-(1-p-tolylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-imineDM-1 (ARN-931) Reaction ofN2-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)-N3-(1-p-tolylethyl)pyridine-2,3-diaminewith cynogen bromide yielded a pale yellow solid (46%); [α]_(D) ²⁰+11.0(c 1.9, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 2H), 8.18-8.02 (m,1H), 7.13-7.03 (m, 5H), 6.95-6.87 (m, 3H), 6.82 (dd, J=8.1, 1.5 Hz, 1H),6.27 (d, J=6.9 Hz, 1H), 5.51 (s, 1H), 4.85 (s, 2H), 4.38-4.15 (m, 1H),4.05 (dd, J=10.9, 2.8 Hz, 1H), 3.57 (dd, J=14.2, 10.4 Hz, 1H), 3.47-3.27(m, 4H), 2.31 (s, 3H), 2.18 (s, 3H), 1.87 (d, J=6.8 Hz, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 150.21, 143.24, 143.05, 138.45, 136.53, 133.05,132.27, 129.62, 129.19, 128.92, 126.92, 121.56, 119.88, 119.04, 96.82,77.28, 67.32, 56.27, 54.85, 33.31, 21.13, 21.02, 17.51. HRMS (ESI-TOF)calcd for C27H33N4O2 [M+H]⁺ 445.2604, found: 445.2606.

3-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)-1-(1-p-tolylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-imineDM-2 (ARN-932) Reaction ofN2-((S)-1-(methoxymethoxy)-3-p-tolylpropan-2-yl)-N3-(1-p-tolylethyl)pyridine-2,3-diaminewith cynogen bromide yielded a viscous oil (47%); [α]_(D) ²⁰−157.6 (c1.44, CHCl₃). H NMR (400 MHz, CDCl₃) δ 8.01 (m, 1H), 7.05 (m, 4H),6.99-6.82 (m, 4H), 6.79 (dd, J=8.0, 5.1 Hz, 1H), 6.67 (dd, J=8.0, 1.4Hz, 1H), 6.25 (d, J=6.8 Hz, 1H), 5.59-5.48 (m, 1H), 4.76 (d, J=6.6 Hz,1H), 4.64 (d, J=6.6 Hz, 1H), 4.54-4.42 (m, 1H), 4.08 (dd, J=10.6, 4.5Hz, 1H), 3.52 (dd, J=13.8, 10.7 Hz, 1H), 3.34-3.18 (m, 4H), 2.36-2.17(m, 6H), 1.81 (d, J=6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 151.78,144.31, 141.24, 137.72, 136.14, 134.30, 133.31, 129.36, 129.11, 129.08,129.03, 126.57, 122.41, 117.46, 96.52, 66.71, 55.55, 53.46, 53.06,33.77, 21.11, 21.09, 16.98. HRMS (ESI-TOF) calcd for C27H33N4O2 [M+H]⁺445.2604, found: 445.2603.

3-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-1-(1-p-tolylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-imineDM-1(ARN-946). Reaction ofN2-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-N3-(1-p-tolylethyl)pyridine-2,3-diaminewith cynogen bromide yielded pale yellow solid (64%); [α]_(D) ²⁰=+10.71(c 4.5, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J=5.1, 1.4 Hz, 1H),7.05-6.91 (m, 5H), 6.85-6.74 (m, 3H), 6.68 (dd, J=8.1, 1.4 Hz, 2H),5.64-5.60 (m, 1H), 4.36-4.14 (m, 1H), 3.84 (ddd, J=22.1, 10.6, 3.9 Hz,2H), 3.64 (ddd, J=10.8, 5.5, 3.4 Hz, 1H), 3.55-3.32 (m, 3H), 3.29 (s,3H), 2.18 (s, 3H), 2.07 (s, 3H), 1.66 (d, J=7.0 Hz, 3H). ¹³C NMR (100MHz, CDCl₃) δ 150.77, 143.44, 142.73, 138.06, 136.30, 133.33, 132.43,129.44, 128.99, 128.96, 126.80, 121.60, 119.58, 118.73, 77.63, 71.42,70.69, 70.23, 59.17, 54.67, 33.24, 21.03, 20.93, 17.02. 19.8. HRMS(ESI-TOF) calcd for C28H35N4O2 [M+H]⁺ 459.2760, found: 459.2790.

3-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-1-(1-p-tolylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-imineDM-2(ARN-947). Reaction ofN2-((S)-1-(2-methoxyethoxy)-3-p-tolylpropan-2-yl)-N3-(1-p-tolylethyl)pyridine-2,3-diaminewith cynogen bromide yielded a pale yellow viscous compound (51%);[α]_(D) ²⁰=−124.97 (c 2.4, CHCl₃). H NMR (400 MHz, CDCl₃) δ 7.96 (dd,J=5.2, 1.4 Hz, 1H), 7.10-6.88 (m, 8H), 6.76 (dd, J=8.0, 5.1 Hz, 1H),6.64 (dd, J=7.9, 1.4 Hz, 1H), 6.47-6.26 (m, 1H), 5.44-5.38 (m, 1H), 4.34(s, 1H), 3.97 (dd, J=10.9, 3.7 Hz, 1H), 3.87 (dt, J=10.9, 4.2 Hz, 1H),3.70 (ddd, J=10.8, 5.4, 3.7 Hz, 1H), 3.54 (t, J=4.8 Hz, 2H), 3.45 (dd,J=13.9, 10.1 Hz, 1H), 3.35 (s, 3H), 3.25 (dd, J=13.8, 6.4 Hz, 1H), 2.28(s, 3H), 2.21 (s, 3H), 1.80 (d, J=6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)δ 151.66, 144.20, 141.29, 137.77, 136.16, 134.22, 133.28, 129.38,129.05, 129.03, 126.69, 122.40, 117.62, 77.36, 71.67, 70.73, 70.33,59.19, 53.21, 33.54, 21.07, 21.05, 16.98. HRMS (ESI-TOF) calcd forC28H35N4O2 [M+H]⁺ 459.2760, found: 459.2811.

1-(1-(6-chloropyridin-3-yl)ethyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-imine (ARN-956): To a solution ofN3-(1-(6-chloropyridin-3-yl)ethyl)-N2-(1-methoxy-3-p-tolylpropan-2-yl)pyridine-2,3-diamine(0.200 g, 0.49 mmol) in MeOH (5 mL) was added cyanogens bromide (3 M inCH₂Cl₂, 0.4 mL, 1.2 mmol). The resulting solution was stirred at roomtemperature for 48 h and after completion of the reaction, the solventswas concentrated under reduced pressure. The remaining solid was mixedwith saturated NaHCO₃ solution (25 mL), extracted with CH₂Cl₂ (3×25 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The flash chromatography on silicagel (1:19 MeOH/CH2CL2) provided the desired1-(1-(6-chloropyridin-3-yl)ethyl)-3-(1-methoxy-3-p-tolylpropan-2-yl)-1H-imidazo[4,5b]pyridin-2(3H)-imine as a brown gel (0.920 g, 80% brs). ¹H NMR (400MHz, CDCl₃) δ 8.28 (d, J=2.6 Hz, 1H), 8.02 (dd, J=5.1, 1.3 Hz, 1H), 7.52(dd, J=8.4, 2.6 Hz, 1H), 7.30-7.22 (m, 1H), 7.01 (d, J=7.9 Hz, 2H), 6.92(d, J=7.8 Hz, 2H), 6.85 (dd, J=7.9, 5.1 Hz, 1H), 6.76 (dd, J=7.9, 1.3Hz, 1H), 5.39 (s, J=5.9 Hz, 1H), 4.17-4.06 (m, 1H), 3.88 (dd, J=10.4,3.3 Hz, 1H), 3.46 (s, 3H), 3.43-3.37 (m, 1H), 3.24 (dd, J=14.0, 6.7 Hz,1H), 2.21 (s, 3H), 1.81 (d, J=7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ151.66, 151.36, 147.64, 144.45, 141.74, 138.08, 136.58, 132.80, 132.55,129.11, 128.88, 124.40, 121.93, 117.85, 116.96, 72.15, 59.39, 56.11,51.17, 33.39, 21.01, 16.78. HRMS (ESI-TOF) calcd for C24H27ClN5O [M+H]⁺436.1904, found: 436.1911.

N3-(1-(6-chloropyridin-3-yl)ethyl)-N2-((S)-1-methoxy-3-p-tolylpropan-2-yl)pyridine-2,3-diamine(ARN-952): N²-(1-methoxy-3-p-tolylpropan-2-yl)pyridine-2,3-diamine (1.0g, 3.69 mmol) was dissolved in DMF (20 mL). At room temperature5-(1-bromoethyl)-2-chloropyridine (1.6 g, 8.6 mmol) and K₂CO₃ (0.77 g,5.5 mmol) were added. The resulting reaction suspension was stirredvigorously at 60° C. till consumption of starting materials. Thesuspension was filtered through a pad of celite and the filter cake waswashed by a small amount of ethyl acetate. The resulting solution wasextracted with EtOAc (3×50 mL) and the combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theflash chromatography on silica gel (1:3 EtOAc/Hexane) provided thedesired product (distereomer 1, 2) as oil (0.920 g, 61%). ¹H NMRDistereomers 1 (400 MHz, CDCl₃) δ 8.34 (d, J=2.5 Hz, 1H), 7.90-7.78 (m,1H), 7.31-7.21 (m, 2H), 7.18-7.06 (m, 2H), 6.96 (d, J=7.7 Hz, 2H),6.45-6.27 (m, 2H), 4.45 (dt, J=13.0, 7.8 Hz, 2H), 3.79-3.56 (m, 2H),3.29 (s, 4H), 3.08 (dd, J=13.9, 6.8 Hz, 1H), 2.19 (s, 3H), 1.72 (d,J=6.7 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 136.1, 132.7, 129.0, 127.6,61.4, 60.4, 49.4, 46.1, 39.3, 32.5, 27.3. ¹H NMR Distereomers 2 (400MHz, CDCl₃) δ 8.27 (d, J=2.5 Hz, 1H), 7.60 (dd, J=8.2, 2.5 Hz, 1H), 7.30(d, J=7.8 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 7.07 (dd, J=6.2, 1.3 Hz, 1H),6.93 (d, J=7.7 Hz, 2H), 6.39-6.23 (m, 2H), 4.75-4.40 (m, 2H), 3.85-3.57(m, 2H), 3.29 (s, 4H), 3.07 (dd, J=13.8, 6.2 Hz, 1H), 2.18 (s, 3H), 1.72(d, J=6.7 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 150.28, 147.89, 144.91,138.01, 136.66, 136.16, 133.95, 132.43, 129.46, 129.06, 124.58, 121.38,116.26, 112.62, 75.04, 59.25, 56.55, 51.23, 36.25, 24.40, 21.01.

Other Examples3-(3-hydroxy-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)pyridin-2(1H)-one(ARN-19)

To a flask equipped with a reflux condenser and stirring bar were added2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(2-methoxypyridin-3-yl)propan-1-ol(0.80 g, 0.20 mmol), anhydrous acetonitrile (5 mL), NaI (0.12 g, 0.80mmol) and Me₃SiCl (0.26 mL, 2.0 mmol). The resulting mixture was stirredat 75° C. for 3.5 h and then cooled to room temperature. 20% NH₄Clsolution (6 mL) was added to the reaction mixture and after theevaporation of most acetonitrile under reduced pressure, the remainingslurry was diluted with water (10 mL) extracted with CH₂Cl₂ (3×25 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the entitled free amineproduct as brown foam (73 mg, 95%); ¹H NMR (400 MHz, CDCl₃) δ 7.36-6.74(m, 11H), 6.04 (t, J=6.6 Hz, 1H), 4.94 (dd, J=35.3, 18.4 Hz, 3H),4.18-3.91 (m, 2H), 3.18 (ddd, J=40.3, 13.2, 7.5 Hz, 2H), 2.27 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 162.18, 154.69, 144.99, 139.95, 137.75,132.17, 129.66, 126.63, 121.09, 120.56, 116.82, 106.93, 106.65, 62.89,55.78, 53.31, 44.96, 28.72, 21.12. HRMS (ESI-TOF) calcd for C23H24N4O2[M+H]⁺ 389.1972, found: 389.1975.

5-(3-hydroxy-2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)pyridin-2(1H)-one(ARN-29). To a flask equipped with a reflux condenser and stirring barwere added2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(6-methoxypyridin-3-yl)propan-1-ol(0.80 g, 0.20 mmol), anhydrous acetonitrile (5 mL), NaI (0.12 g, 0.80mmol) and Me₃SiCl (0.26 mL, 2.0 mmol). The resulting mixture was stirredat 75° C. for 4 h and then cooled to room temperature. 20% NH₄Clsolution (5 mL) was added to the reaction mixture and after theevaporation of most acetonitrile under reduced pressure, the remainingslurry was diluted with water (10 mL) extracted with CH₂Cl₂ (3×25 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the entitled free amineproduct as brown foam (0.60 g, 78%); ¹H NMR (400 MHz, CDCl₃+MeOH) δ7.56-6.82 (m, 10H), 6.28 (dd, J=9.4, 2.8 Hz, 1H), 5.24 (d, J=3.0 Hz,2H), 5.21-5.13 (m, 1H), 4.76 (d, J=8.6 Hz, 1H), 4.25-4.00 (m, 2H),3.21-2.94 (m, 2H), 2.22 (s, 3H). ¹³C NMR (100 MHz, CDCl₃+MeOH) δ 163.29,151.16, 143.73, 138.36, 134.02, 130.21, 129.98, 129.83, 126.54, 123.83,123.71, 120.01, 115.55, 109.95, 61.76, 53.45, 46.36, 29.57, 20.98.

3-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-phenylpropan-1-olhydrobromide. To a solution of3-((2-aminophenyl)amino)-2-phenylpropan-1-ol (0.0440 g, 0.18 mmol) inMeOH (3 mL) was added cyanogen bromide (3 M in DCM, 0.10 mL, 0.30 mmol).The resulting solution was stirred at room temperature overnight andafter the evaporation of solvents, the residue was mixed with saturatedNaHCO₃ solution (after which the aqueous layer's pH is about 8-9) andthen extracted with DCM (3×30 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the3-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-phenylpropan-1-olintermediate as a dark brown gel.

To a flask equipped with a reflux condenser and stirring bar were addedthe above3-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-phenylpropan-1-olintermediate, 2-butanone (7 mL) and 1-(bromomethyl)-4-methylbenzene(0.0412 g, 0.22 mmol). The resulting mixture was stirred at 75° C. for 8h and then cooled to room temperature. After the evaporation of most ofthe 2-butanone under reduced pressure, the residue was sonicated withEt₂O (20 mL) and then the supernatant was removed using pipette. Thisprocedure was repeated three times and the remaining solid was driedunder vacuum to obtain the entitled amine HBr salt product as brown foam(0.0352 g, 43% two steps). ¹H NMR (400 MHz, CD₃OD) δ 7.43-7.37 (m, 1H),7.32-7.19 (m, 6H), 7.19-7.11 (m, 4H), 6.94 (d, J=8.2 Hz, 2H), 5.28 (s,2H), 4.64 (dd, J=15.1, 5.8 Hz, 1H), 4.50 (dd, J=15.1, 9.3 Hz, 1H),4.05-3.83 (m, 2H), 3.54-3.41 (m, 1H), 2.31 (s, 3H). ¹³C NMR (100 MHz,CD₃OD) δ 149.9, 138.2, 138.0, 130.7, 129.7, 129.5, 129.3, 128.4, 127.9,127.4, 126.3, 123.8, 123.8, 110.6, 110.4, 62.7, 46.2, 45.8, 45.5, 19.7.

2-(3-(1-hydroxy-3-(p-tolyl)propan-2-yl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(p-tolyl)ethan-1-onehydrobromide. To a flask equipped with a reflux condenser and stirringbar were added2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol(0.0470 g, 0.17 mmol), 2-butanone (7 mL) and2-bromo-1-(p-tolyl)ethan-1-one (0.0500 g, 0.23 mmol). The resultingmixture was stirred at 75° C. for 15 h and then cooled down to roomtemperature. After the evaporation of most of the 2-butanone underreduced pressure, the residue was sonicated with Et₂O (20 mL) and thenthe supernatant was removed using pipette. This procedure was repeatedthree times and the remaining solid was dried under vacuum to obtain theentitled amine HBr salt product as brown foam (0.0602 g, 73%). ¹H NMR(400 MHz, CD₃OD) δ 8.04 (d, J=7.8 Hz, 2H), 7.41 (d, J=6.4 Hz, 2H),7.36-7.14 (m, 3H), 7.12-6.77 (m, 5H), 5.80 (dd, J=31.8, 18.7 Hz, 2H),4.31 (dd, J=12.1, 6.9 Hz, 1H), 4.09 (dd, J=12.1, 3.2 Hz, 1H), 3.46-3.34(m, 1H), 3.23 (dd, J=14.5, 5.0 Hz, 1H), 2.45 (s, 3H), 2.35-2.03 (m, 1H),2.18 (s, 3H). ¹³C NMR (100 MHz, CD₃OD) δ 193.8, 155.1, 149.5, 140.2,137.2, 135.5, 133.3, 132.8, 132.7, 132.5, 132.3, 132.2, 127.6, 127.5,113.7, 65.4, 65.1, 53.1, 36.9, 24.4, 23.6.

2-(2-imino-3-(4-methylphenethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-(p-tolyl)butan-1-ol.To a solution of 2-((2-aminophenyl)amino)-4-(p-tolyl)butan-1-ol (0.2091g, 0.77 mmol) in MeOH (12 mL) was added cyanogen bromide (3 M in DCM,0.31 mL, 0.93 mmol). The resulting solution was stirred at roomtemperature for 19 h and after the evaporation of solvents, the residuewas mixed with saturated NaHCO₃ solution (after which the aqueouslayer's pH is about 8-9) and then extracted with DCM (3×30 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-(p-tolyl)butan-1-olintermediate as a dark brown gel which was dissolved in DCM (8 mL). Thisintermediate solution (4 mL) was concentrated for next step withoutfurther purification. To a flask equipped with a reflux condenser andstirring bar were added the above2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-4-(p-tolyl)butan-1-olintermediate, 3-hexanone (6 mL) and 1-(2-bromoethyl)-4-methylbenzene(0.0895 g, 0.45 mmol). The resulting mixture was stirred at 120° C. for24 h and then cooled to room temperature. After the evaporation of mostof the 3-hexanone under reduced pressure, the residue was sonicated withEt₂O (20 mL) and then the supernatant was removed using pipette. Thisprocedure was repeated three times and the remaining solid was mixedwith saturated NaHCO₃ solution (30 mL), extracted with DCM (3×30 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the entitled free amineproduct as a brown gel (0.0664 g, 41% two steps). ¹H NMR (400 MHz,CDCl₃) δ 7.13-7.02 (m, 8H), 7.00-6.89 (m, 3H), 6.80-6.74 (m, 1H),6.73-6.67 (m, 1H), 4.15-4.05 (m, 1H), 4.01 (d, J=3.2 Hz, 2H), 3.91 (td,J=7.4, 2.2 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.75-2.63 (m, 1H), 2.61-2.35(m, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 2.28 (s, 1H). ¹³C NMR (100 MHz,CDCl₃) δ 154.3, 138.0, 136.6, 135.4, 134.5, 131.4, 131.2, 129.5, 129.0,128.6, 128.2, 121.0, 120.6, 107.1, 106.6, 63.3, 56.5, 43.5, 33.6, 31.8,28.7, 21.0, 21.0.

2-(2-imino-3-(4-methylphenethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.To a flask equipped with a reflux condenser and stirring bar were added2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol(0.0566 g, 0.20 mmol), 3-hexanone (4 mL) and1-(2-bromoethyl)-4-methylbenzene (0.0641 g, 0.32 mmol). The resultingmixture was stirred at 120° C. for 27 h and then cooled down to roomtemperature. After the evaporation of most of the 3-hexanone underreduced pressure, the residue was sonicated with Et₂O (20 mL) and thenthe supernatant was removed using pipette. This procedure was repeatedthree times and the remaining solid was mixed with saturated NaHCO₃solution (30 mL), extracted with DCM (3×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the entitled free amine product as a brown gel(0.0407 g, 51%). ¹H NMR (400 MHz, CDCl₃) δ 7.19-6.99 (m, 9H), 6.96-6.88(m, 2H), 6.77-6.67 (m, 2H), 4.22 (s, 1H), 4.01 (d, J=12.5 Hz, 1H),3.95-3.84 (m, 3H), 3.41 (dd, J=13.4, 8.4 Hz, 1H), 3.05 (dd, J=13.4, 7.0Hz, 1H), 2.94 (t, J=7.5 Hz, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.24 (s,1H). ¹³C NMR (100 MHz, CDCl₃) δ 154.4, 136.6, 135.9, 135.3, 134.6,131.4, 131.2, 129.5, 129.2, 129.1, 128.6, 120.9, 120.5, 106.9, 106.5,62.5, 59.5, 43.5, 33.6, 33.4, 21.1, 21.0.

2-(2-imino-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-amine.To a solution of tert-butyl(2-((2-aminophenyl)amino)-3-(p-tolyl)propyl)carbamate (0.0748 g, 0.21mmol) in MeOH (5 mL) was added cyanogen bromide (3 M in DCM, 0.09 mL,0.27 mmol). The resulting solution was stirred at room temperature for3.5 h and after the evaporation of solvents, the residue was mixed withsaturated NaHCO₃ solution (after which the aqueous layer's pH is about8-9) and then extracted with DCM (3×30 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the tert-butyl(2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamateintermediate as a dark brown gel which was used directly for next stepwithout further purification. To a flask equipped with a refluxcondenser and stirring bar were added the above tert-butyl(2-(2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propyl)carbamateintermediate, 2-butanone (7 mL) and 1-(bromomethyl)-4-methylbenzene(0.0533 g, 0.29 mmol). The resulting mixture was stirred at 75° C.overnight and then cooled down to room temperature. After theevaporation of most of the 2-butanone under reduced pressure, theresidue was dissolved in 1, 4-dioxane (3 mL) and conc. HCl (0.7 mL) wasadded. The resulting reaction mixture was stirred at room temperaturefor 1 h and after the evaporation of solvents and excess HCl, theresidue was sonicated with Et₂O (25 mL) and then the supernatant wasremoved using pipette. This procedure was repeated three times and theremaining solid was mixed with saturated NaHCO₃ solution (30 mL),extracted with DCM (3×30 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe entitled free amine product as a brown gel (0.0810 g, >95% threesteps). ¹H NMR (400 MHz, CDCl₃) δ 7.18-6.81 (m, 11H), 6.72 (d, J=7.4 Hz,1H), 5.14-4.79 (m, 2H), 4.65 (s, 1H), 3.47 (s, 1H), 3.37-3.18 (m, 1H),3.17-3.05 (m, 2H), 2.74-2.33 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 155.3, 137.2, 135.9, 134.7, 132.8, 131.7, 129.5,129.4, 129.1, 128.9, 128.6, 126.6, 120.5, 120.4, 106.8, 59.6, 44.8,43.4, 35.6, 21.1, 21.1.

2-(2-imino-6-methyl-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.Cyclization of 2-((2-amino-5-methylphenyl)amino)-3-(p-tolyl)propan-1-ol,followed by alkylation with 4-methylbenzyl bromide (Procedure E) yieldedthe title product (68% two steps). ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.12(m, 4H), 7.08 (d, J=8.2 Hz, 2H), 7.02 (d, J=7.7 Hz, 2H), 6.71 (d, J=7.2Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.54 (s, 1H), 4.88 (d, J=5.6 Hz, 2H),4.33-4.18 (m, 1H), 4.04 (d, J=12.5 Hz, 1H), 3.92 (dd, J=12.4, 4.7 Hz,1H), 3.42 (dd, J=13.4, 8.2 Hz, 1H), 3.10 (dd, J=13.4, 7.2 Hz, 1H), 2.33(s, 3H), 2.30 (s, 3H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.9,137.7, 135.8, 135.4, 132.2, 131.6, 130.9, 129.6, 129.5, 129.3, 129.0,126.6, 121.0, 107.8, 106.5, 62.6, 59.6, 45.1, 33.4, 21.4, 21.1, 21.0.

2-(2-imino-6-methoxy-3-(4-methylbenzyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-ol.To a flame-dried flask were added lithium aluminum hydride (0.0932 g,2.45 mmol) and anhydrous THF (8 mL) at 0° C., followed by addition ofethyl 2-((5-methoxy-2-nitrophenyl)amino)-3-(p-tolyl)propanoate (0.4244g, 1.19 mmol) in anhydrous THF (4 mL) under argon. The resultingreaction mixture was stirred at 0° C. for 80 min and 1 N KOH solution(12 mL) was added dropwise at 0° C. to quench the reaction while addingTHF (12 mL) at the same time. Upon the addition of KOH solution, themixture was stirred for 30 more min at rt and was condensed underreduced pressure to evaporate most of the THF. The residue was thenmixed with water (60 mL) and extracted with EtOAc (3×60 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford a mixture of2-((5-methoxy-2-nitrophenyl)amino)-3-(p-tolyl)propan-1-ol (major one)and 2-((2-amino-5-methoxyphenyl)amino)-3-(p-tolyl)propan-1-ol (minorone). To a 50 mL flask were added the mixture above, methanol (10 mL)and Pd/C (3 spatula, 10% on active carbon). The reaction flask wassealed by a septum and after the removal of air using vacuum, a hydrogenballoon was fitted on the top of the septum. The reaction suspension wasthen stirred at room temperature for 4 h and was filtered through a padof celite. The filtrate was concentrated under reduced pressure and theresidue was purified through flash chromatography on silica gel (1:19Methanol/DCM) to afford the2-((2-amino-5-methoxyphenyl)amino)-3-(p-tolyl)propan-1-ol (0.0348 g)which was used for next step. To a solution of2-((2-amino-5-methoxyphenyl)amino)-3-(p-tolyl)propan-1-ol (0.0348 g,0.12 mmol) in MeOH (4 mL) was added cyanogen bromide (3 M in DCM, 0.05mL, 0.15 mmol). The resulting solution was stirred at room temperatureovernight and after the evaporation of solvents, the residue was mixedwith saturated NaHCO₃ solution (after which the aqueous layer's pH isabout 8-9) and then extracted with DCM (3×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the2-(2-imino-6-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-olintermediate as a dark brown gel which was used directly for next stepwithout further purification. To a flask equipped with a refluxcondenser and stirring bar were added the above2-(2-imino-6-methoxy-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-3-(p-tolyl)propan-1-olintermediate, 2-butanone (5 mL) and 1-(bromomethyl)-4-methylbenzene(0.0291 g, 0.16 mmol). The resulting mixture was stirred at 75° C. for 9h and then cooled down to room temperature. After the evaporation ofmost of the 2-butanone under reduced pressure, the residue was sonicatedwith Et₂O (20 mL) and then the supernatant was removed using pipette.This procedure was repeated three times and the remaining solid wasmixed with saturated NaHCO₃ solution (30 mL), extracted with DCM (3×30mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the entitled free amineproduct as a brown gel (0.0303 g, 6% four steps). ¹H NMR (400 MHz,CDCl₃) δ 7.19-7.06 (m, 6H), 7.05-6.96 (m, 2H), 6.62 (d, J=8.4 Hz, 1H),6.44 (dd, J=8.4, 2.3 Hz, 1H), 6.31 (s, 1H), 4.85 (d, J=4.0 Hz, 2H), 4.19(q, J=7.0 Hz, 1H), 4.06 (d, J=11.8 Hz, 1H), 3.94 (dd, J=12.4, 4.7 Hz,1H), 3.72 (s, 3H), 3.38 (dd, J=13.4, 7.7 Hz, 1H), 3.15 (dd, J=13.5, 7.5Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 155.3,155.2, 137.7, 135.9, 135.4, 132.5, 132.3, 129.7, 129.3, 129.1, 126.6,125.8, 106.7, 105.3, 95.0, 62.7, 59.8, 56.0, 45.1, 33.4, 21.1, 21.0.

Other Synthesis Schemes

IP Accumulation Assay

HEK293 cells stably expressing OX2R are transfected with Gq alphaconstruct (6.4 ug per 10 cm dish) using Lipofectamine 3000(ThermoFisher). 24 hours after transfection, cells are plated onpoly-lysine-coated 96-well plates at 30,000 cells per well inInositol-free DMEM+5% FCS with 5 uCi per ml Myo-[2-3H] Inositol (PerkinElmer). Plates are incubated at 37° C. O/N in 8% C02 tissue cultureincubator. Agonists are diluted serially in HBSS containing 10 mMLithium Chloride. After removal of culture media, agonist solutions areadded to the cells (100 ul/well) and incubated at 37° C. 45 min in 8%C02 incubator. Agonist solution is removed and cells are lysed on icewith 10 mM Formic Acid (40 ul/well) for 30 minutes. SPA Poly Lysine YSIbeads (Perkin Elmer, cat #RPNQ0010) are added to the wells and mixed ona shaker for 30 minutes before reading on a Microbeta scintillationcounter. Positive control curves run with all screens: orexin B andYanagisawa (J. Med. Chem. 2015) agonist.

TABLE 1 SAR: Ranking (ignoring 100 uM data points for all assays due totoxicity) Micro- somes stability T_(1/2) (min) and Clint (ul/min/mgprotein); PK; Compound Caco-2 cell perme- ability Papp value (Unit:10e-6 cm/s); BBB (Brain AUC: Page Blood No. AUC) of [From H- pKa EC₅₀ PKData CLog TPSA MW B- (from CNS graph- (5 or 10 Structure Title ClogP D(Å) (g/mol) D imine) MPO EC₅₀ ics mpk IV)]

ww3- 309 483.4 +  1

ww4- 002  2.52521 0.86 79.66 388.5 3  9.18 4.4 —  1

ww4- 23  4.56221 2.78 72.15 402.5 2  8.76 3.6 —  1

ww4- 29  5.73821 3.61 50.56 385.51 2  9.22 2.9 ++ 1, 3, 5, 7, 19, 26, 42Papp A-->B: 2.36; Papp B-->A: 2.36; Eflux ratio: 1.0

ww4- 30  5.23921 3.07 50.56 371.48 2  9.25 3.3 —  1

ww4- 67  3.74221 1.97 62.92 372.47 2  9.14 4.5 —  2

ww4- 86  4.56221 2.48 72.15 402.5 2  9.01 3.7 —  2

ww4- 89  2.5252 0.89 79.66 388.47 3  9.19 4.4 —  2 solubility issuealong with tauto- meriza- tion, only proton NMR and LC-MS

ww4- 103 452.4 —  2

ww4- 105 (impure version of DM- 68)  4.5122 3.15 72.15 412.49 2  8.483.6 +  2 80% purity; DM-68 is the pure version of ww4- 105

ww4- 106 494.43 —  2

ww4- 143  5.23921 3.05 50.56 371.48 2  9.28 3.3 ++  3 named ww4-123 intest graphics and summary

ww4- 163  6.11321 3.77 50.56 399.54 2  9.39 2.6 —

ww4- 169  6.49221 4.27 50.56 413.57 2  9.31 2.5 —

ww4- 170  6.11721 4.12 50.56 399.54 2  9.13 2.7 —

ww4- 187  6.23721 4.1 50.56 399.54 2  9.25 2.6 ++  5

ww4- 190  5.81521 1.4 56.35 384.53 3  9.1 3.4 ++  5

ww4- 198  5.65721 3.66 59.79 415.54 2  8.96 2.8 NA

ww4- 204  6.23721 4.1 50.56 399.54 2  9.25 2.6 NA

ww4- 213  5.96821 4.41 50.56 449.63 2  8.83 2.4

ww4- 230 (impure version of ww4- 234)  6.04721 3.99 50.56 399.54 2  9.262.6 + 19 Not pure; ww4-234 is the pure version

ww4- 234 (pure version of ww4- 230)  6.04721 3.99 50.56 399.54 2  9.262.6 + 19 mixture of two dia- stereo- mer; R config- uration at the lowerchiral center

ww4- 273  6.419 4.2 30.33 373.48 1  9.11 2.7 —  6

ww4- 276  6.61421 4.29 39.07 399.54 1  8.67 3.2 ++  6 Papp A-->B: 2.19;Papp B-->A: 5.47; Eflux ratio: 2.50

ww4- 281  5.67031 3.21 59.43 426.56 2  9.37 2.7 ++ 6, 7, 9, 10, 11, 12,13, 15, 16, 18

ww4- 290  6.638 4.71 30.33 387.5 1  8.96 2.7 +  6

ww4- 301  5.46221 3.4 50.56 389.47 2  8.82 3.2 +  7

ww5- 17  6.568 4.6 30.33 387.5 1  9.09 2.6

ww5- 29  7.78331 6.26 74.24 526.68 1  6.29 2.8 +  9 aka ww5-81

ww5- 34  8.31231 6.96 74.24 540.71 1  6.27 2.8 +  9

ww5- 40  6.19931 3.93 59.43 440.59 2  9.34 2.3 ++ 9, 10

ww5- 43  7.40231 5.2 59.43 488.64 2  9.18 2 + 10

ww5- 45  6.25431 4.03 59.43 452.6 2  9.31 2.2 ++ 10

ww5- 52  6.77931 5.82 59.43 480.54 2  9.06 2.1 ++ 11

ww5- 60  7.39231 5.22 59.43 502.66 2  9.13 1.9 ++ 12, 14

ww5- 66  5.57651 3.15 59.43 412.54 2  9.37 2.9 ++ 13

ww5- 74  7.31131 5.08 68.66 532.69 2  9.12 1.9 + 14

ww5- 79  6.40797 4.45 47.94 424.55 1  8.17 (am- ide) 3.3 ++ 13

ww5- 80  6.68811 3.13 33.57 412.58 1  9.58 2.8 ++ 13

ww5- 90  6.59081 4.4 59.43 452.6 2  9.3 2.2 + 15

ww5- 73  5.67031 3.21 59.43 426.56 2  9.37 2.7 + 16 R-enan- tiomer ofww4-281

ww5- 98  5.67031 3.21 59.43 426.56 2  9.37 2.7 ++ 16, 18 Papp A-->B:0.45; Papp B-->A: 9.05; Eflux ratio: 20.00; S-enan- tiomer of ww4- 281

ww5- 100  5.89531 4.04 71.79 503.65 2  9.09 2 + 14, 23

ww5- 111  5.89531 4.04 71.79 503.65 2  9.09 2 ++ 17, 23

ww5- 123  6.27271 2.67 53.8 442.61 2  9.48 2.8 — 18

ww5- 126 521.5 ++ 18 Papp A-->B: 2.27; Papp B-->A: 13.63; Eflux ratio:6.00

ww5- 150  6.04721 3.99 50.56 399.54 2  9.26 2.6 +++ 19 mixture of twodiastereo- mer; S config- uration at the lower chiral center

ww5- 163  5.81931 2.82 79.66 456.59 3  9.35 2.4 ++++ 20, 22, 24, 41mixture of two diastereo- mer; S config- uration at the lower chirlacenter

ww5- 166  5.81931 2.82 79.66 456.59 3  9.35 2.4 +++ 20, 22 diastereo-mer A

ww5- 167 (impure version of ww5- 189)  5.81931 2.82 79.66 456.59 3  9.352.4 ++++ 20, 21 85% diastereo- mer B mixed with about 15% diastereo- merA

ww5- 189 (pure version of ww5- 167)  5.81931 2.82 79.66 456.59 3  9.352.4 ++++ 22, 24, 25, 26, 27, 29, 30, 31, 33, 34, 35, 42 Plasma PK(5mg/kg IV, Female CD-1 Mice), Estimate Plasma: HL_ Lambda_z 230.35342min, Tmax 10 min, Cmax 600.33333 ng/mL, AUClast 41473.919 min*ng/ml,Vz_F_obs 904.08626 mL, Cl_F_obs 2.7204495 mL/min; Brain PK (5mg/kg IV,Female CD-1 Mice), Estimate Brain: HL_ Lambda_z 728.55418 min, Tmax 30min, Cmax 15.293333 ng/mL, AUClast 11291.545 min*ng/ml; Papp A-->B:0.25; Papp B-->A: 6.37; Eflux ratio: 25.00; 0.3:1; diastereo- mer B(injected into mice by Noelle; ww5-167 is the mixture of 85% diastereo-mer B and 15% diastereo- mer A)

ww5- 171  6.16531 4.39 85.45 517.68 4  9.14 1.4 ++ 21

ww5- 177  6.11531 4.44 85.45 517.68 4  9.08 1.5 ++ 22

ww5- 179  6.16531 4.43 85.45 517.68 4  9.09 1.5 ++ 22

ww5- 188  5.89531 4.43 71.79 503.65 2  9.09 2 ++ 23, 25 Papp A-->B:1.28; Papp B-->A: 8.51; Eflux ratio: 6.67

ww5- 190 (aka KM- 4-214- 1)  5.5103 2.43 79.66 442.56 3  9.31 2.7 +++aka KM-4- 214-1

ww5- 194  5.14331 1.56 85.45 441.58 4  9.36 2.7 ++ 23

ww5- 205  6.74731 3.62 79.66 484.64 3  9.47 1.7 ++ 24

ww5- 209  6.26331 3.18 79.66 482.63 3  9.44 2 ++++ 24, 25, 41 PappA-->B: 0.37; Papp B-->A: 7.46; Eflux ratio: 20.00; mixture of twodiastereo- mers

ww5- 210  5.48451 1.43 71.46 455.61 3  9.41 2.8 ++ 24

ww5- 218  5.61131 3.04 79.66 470.62 3  9.21 2.3 ++ 25

ww5- 222  4.93831 4.61 84.15 504.64 2  9.06 2 + 25

ww5- 254  6.2043 4.82 71.79 517.68 2  9.12 1.9 ++ 41 mixture of rotamers

ww5- 255  6.6483 5.17 71.79 543.72 2  9.21 1.9 ++ 41 mixture of rotamers

ww5- 307  6.46331 4.51 59.43 494.56 2  9.06 2 ++ 26

ww5- 308  5.84331 3.34 59.43 444.55 2  9.28 2.6 ++ 26, 28 Papp A-->B:3.05; Papp B-->A: 8.72; Eflux ratio: 2.86

ww6- 002  6.17531 3.59 81.02 479.58 2  9.1 2.3 ++ 27

ww6- 004  5.95701 3.37 62.67 455.61 2  9.3 2.5 ++ 27

ww6- 10  6.57831 4.3 68.66 478.6 2  9.13 2.1 ++ 28

ww6- 13  6.23591 3.14 68.66 468.6 2  9.25 2.5 ++ 29

ww6- 15  7.49831 4.58 71.79 503.65 2  9.08 2 + 29

ww6- 16  7.15831 4.95 71.79 503.65 2  9.1 2 + 29

ww6- 23  5.82004 3.46 84.15 490.61 2  9.1 2.3 ++ 30

ww6- 33  5.10504 3.18 79.66 442.56 3  8.6 2.7 ++ 31

ww6- 34  6.18811 3.55 81.02 479.58 2  9.1 2.3 ++ 31

ww6- 35  6.11711 3.86 81.02 493.61 2  9.07 2.1 ++ 31

ww6- 36  6.77801 5.4 76.5 498.59 2  9.02 2 ++ 31

ww6- 39  6.06931 2.79 81.37 453.59 3  9.31 2.4 ++++ 32

ww6- 40  6.26208 3.41 75.03 506.65 2  9.12 2.2 + 32

ww6- 56  7.24861 4.98 39.56 439.6 1  9.37 2.6 ++++ 33, 34, 38, 40mixture of two diastereo- mers

ww6- 61  7.24861 4.98 39.56 439.6 1  9.37 2.6 ++++ 34, 36, 37, 39 T1/2(min) = 19 and Clint (ul/min/mg protein) = 17.01; Plasma PK (5 mpk IV,female CD1), Estimate Plasma: HL_ Lambda_z 74.038003 min, Tmax 10 min,Cmax 841 ng/mL, AUClast 59182.833 min*ng/ml, Vz_F_obs 205.30839 mL,Cl_F_obs 1.9221065 mL/min; Brain PK (5 mpk IV, female CD1 mice) EstimateBrain: HL_ Lambda_z 134.09403 min, Tmax 30 min, Cmax 143.31 ng/mL,AUClast 38968.815 min*ng/ml; Papp A-->B: 0.66; Papp B-->A: 1.97; Efluxratio: 3.00; 0.65:1; diastereo- mer A (x-ray crystallo- graphy forabsolute config- uration)

ww6- 60  7.24861 4.98 39.56 439.6 1  9.37 2.6 +++ 34 diastereo- mer B

ww6- 67  6.32001 4.28 48.79 443.59 1  9.13 2.7 ++ 35 Papp A-->B: 2.93;Papp B-->A: 4.88; Eflux ratio: 1.67; aka A RN-422

ww6- 71  6.24941 4.35 48.79 429.56 1  9.17 2.8 ++ 36 Papp A-->B: 3.10;Papp B-->A: 3.10; Eflux ratio: 1.0

DM- 006  6.2372 4.1 50.56 399.54 2  9.25 2.6 —  2 In summary, namedDM-005

DM- 13  4.5622 2.51 72.15 402.5 2  8.98 3.7 —

DM- 14  4.8642 2.9 50.56 357.46 2  9.1 3.6 —

DM- 18  5.3632 3.45 50.56 371.48 2  9.06 3.2 —

DM- 19  6.1222 4.29 50.56 439.48 2  8.83 2.5 —

DM- 20  4.5622 2.51 72.15 402.5 2  8.98 3.7 —

DM- 21  4.5622 2.78 72.15 402.5 2  8.76 3.6

DM- 23  2.5252 1.18 79.66 388.47 3  9.07 4.4 —  3

DM- 24  2.5252 0.88 79.66 388.47 3  9.2 4.4 —  3

DM- 27  4.8852 2.98 50.56 377.51 2  9.09 3.4 +  3

DM- 28  5.2982 3.68 59.79 429.44 2  8.37 3 —  3

DM- 29  5.8622 3.94 50.56 385.51 2  9.09 2.8 +  3

DM- 65  6.4956 4.23 39.56 399.54 1  9.25 2.9 ++

DM- 66  6.0472 3.99 50.56 399.54 2  9.26 2.6 ++ 5, 19 a mixture of twopairs of enan- tiomers

DM- 68 (pure version of ww4- 105)  4.5122 3.15 72.15 412.49 2  8.48 3.6++  5 pure version of ww4-105

WM- 120  6.9993 4.41 71.79 489.62 2  9.13 2 ++ 42

WM- 126  6.8773 4.33 62.67 491.64 2  9.17 2 ++ 42

WM- 132  6.8773 4.33 62.67 491.64 2  9.17 2 ++ 26 s-enan- tiomer ofWM-126

WM- 136  6.6493 4.03 71.79 489.62 2  9.13 2 ++ 27, 28

WM- 138  6.5783 4.38 68.66 478.6 2  9.13 2.1

WM- 142  6.6493 4.02 71.79 489.62 2  9.13 2 ++ 30

WM- 144  7.1219 4.82 96.18 529.65 3  9.05 1.4 ++ 32

WM- 146  6.6658 4.25 71.79 509.67 2  9.03 2

WM- 148  6.3723 3.93 59.43 458.58 2  9.26 2.2

KM-4- 173-3  5.668 4.58 69.72 463.6 1 10.62 (sul- fon- a- mide) 2.1 +  9

KM-4- 174-2  7.2845 6.69 69.72 525.67 1 10.18 (sul- fon- a- mide) 1.8 — 9

KM-4- 180-1  6.361 3.37 76.5 476.64 2  9.16 2.4 ++ 10

KM-4- 181-1  6.416 3.65 76.5 488.65 2  9.13 2.2 ++ 10 In summary namedKM-1811

KM-4- 182-2  7.4485 5.11 76.5 524.68 2  8.98 2 + 10 In summary namedKM-1822

KM-4- 189- org  5.832 2.84 76.5 462.61 2  9.17 2.8 ++ 31 Papp A-->B:3.06; Papp B-->A: 9.19; Eflux ratio: 3.00

KM-4- 190- org  6.3787 3.87 68.66 442.56 2  9.3 2.3 ++ 11

KM-4- 191- org  6.9077 4.27 68.66 456.59 2  9.25 2.2 ++

KM-4- 196-1  6.67 3.95 76.5 490.67 2  9.14 2 ++ 12

KM-4- 197-1  7.4616 4.9 76.5 538.71 2  8.95 2 ++ 12

KM-4- 198-1  7.941 6.37 76.5 516.58 2  8.91 2 — 12

KM-4- 207-1  5.2531 3.87 79.66 428.54 3  9.38 2.1 +

KM-4- 208-1  5.3224 2.88 85.45 427.55 4  9.36 2.4 +++ 14, 15, 16, 27Papp A-->B: 0.07; Papp B-->A: 4.58; Eflux ratio: 66.67

KM-4- 209-1  7.8913 5.73 59.43 516.69 2  9.13 1.9 + 14

KM-4- 213-1  6.0784 3.12 71.46 441.58 3  9.33 2.4 ++

KM-4- 214-1 (differ- ent batch ww5- 190)  5.5103 2.43 79.66 442.56 3 9.31 2.7 +++ 15, 17, 18, 20, 21, 22 23, 24, 25, ww5- 190 = differentbatch of, KM-4- 214-1

KM-4- 215-1  5.8489 3.11 68.66 456.59 2  9.26 2.6 ++

KM-4- 229-2  8.6983 6.6 59.43 571.55 2  8.93 2 ++

KM-4- 237-2  6.0909 2.88 62.67 469.63 2  9.24 2.7 ++ 17

KM-4- 267-3 (impure version of KM-4- 287)  5.5103 2.43 79.66 442.56 3 9.31 2.7 +++ 19 KM-4- 287 is the pure version

KM-4- 273-1  5.8193 3.02 79.66 456.59 3  9.28 2.3 ++

KM-4- 281-1  5.8193 3.02 79.66 456.59 3  9.28 2.3 ++ 21 Papp A-->B:0.21; Papp B-->A: 8.48; Eflux ratio: 40.00

KM-4- 287 (pure version of KM-4- 267-3)  5.5103 2.43 79.66 442.56 3 9.31 2.7 +++ 21, 26, 28 Papp A-->B: 0.39; Papp B-->A: 5.90; Efluxratio: 15.00; KM-4- 287 is the pure version of KM-4- 267-3

KM-4- 289  5.5103 2.43 79.66 442.56 3  9.31 2.7 + 21

ww6- 90  7.3336 5.09 39.56 427.59 1  9.35 2.7 ++++ 38 mixture of twodiastereo- mers

ww6- 106  6.7686 6.38 39.56 467.54 1  7.89 3 ++ 39 ratio of twodiastereo- mers is 2:3

ww6- 112  7.8076 5.39 39.56 453.28 1  9.41 2.4 +++ 40 mixture of twodiastereo- mers

ww6- 130  7.9566 5.59 39.56 467.66 1  9.49 2.3 + 43 mixture of twodiastereo- mers in the form of rotamers

ww6- 131  6.6276 4.8 39.56 431.56 1  8.87 2.9 +++ 43 mixture of twodiastereo- mers

ww6- 157  6.35621 4.37 50.56 413.6 2  9.32 0 44 mixture of twodiastereo- mers

ww6- 162 551.5 2 +++ 44 mixture of two diastereo- mers

ww6- 185  4.62031 2.2 92.02 478 3  8.99 +++ 45 mixture of two diastereo-mers

ww6- 187  6.35621 4.37 50.56 413.6 2  9.32 +++ 45 mixture of twodiastereo- mers

ww6- 230  4.17291 4.36 95.58 466.59 2  7.53 — 46 diastereo- mer B

ww6- 236  4.17291 4.36 95.58 466.59 2  7.53 — 46 diastereo- mer A

ww6- 248  5.74831 2.95 47.4 445.63 1  9.71 +++ 46

ww6- 266  4.03581 4.6 86.71 439.6 2  7.51 + 47 diastereo- mer D; only HNMR

ww6- 268- first (mix- ture of 2 dia- stereo- mers)  4.03581 4.6 86.71439.6 2  7.51 + 47 diastereo- mer A and C (3.4:1); only H NMR

ww6- 268- second  4.03581 4.6 86.71 439.6 2  7.51 + 47 diastereo- mer B;only H NMR

ww6- 272  4.87361 4.69 66.48 409.54 1  8.25 + 48 diastereo- mer A

ww6- 273  4.87361 4.69 66.48 409.54 1  8.25 +++ 48 diastereo- mer B

ww6- 288- second  5.96071 6.1 42.69 430.61 1  7.76 ++ 49 diastereo- merA

ww6- 289- second  5.96071 6.1 42.69 430.61 1  7.76 ++++ (page 49); +++(page 51) 49 diastereo- mer B

ww6- 306  4.25131 3.74 59.76 446.61 1  7.95 + 50 Ratio 2.1:1; Mixture oftwo sulfoxide diastereo- mers; from diastereo- mer A precursor

ww6- 308  4.15891 3.93 76.83 462.61 1  7.84 + 50 diastereo- mer A

ww7- 002  4.15891 3.93 76.83 462.61 1  7.84 +++ 51 diastereo- mer B

ww7- 003  4.25131 3.74 59.76 446.61 1  7.95 +++ 51 Ratio 4.4:1; Mixtureof two sulfoxide diastereo- mers; from diastereo- mer B precursor

ww7- 31  4.03581 4.6 86.71 439.6 2  7.51 + 52, 53 Diastereo- mer C

ww7- 32 (aka ww6- 266)  4.03581 4.6 86.71 439.6 2  7.51 + 52, 53Diastereo- mer D

ww7- 39  4.03581 4.6 86.71 439.6 2  7.51 + 53 Diastereo- mer A

ww7- 40 (aka ww6- 268- second)  4.03581 4.6 86.71 439.6 2  7.51 + 53Diastereo- mer B

ww7- 51  6.85061 5.47 39.56 449.6 1  8.41 ++ 54

WZ-I- 30-3  6.19 4.5 62.92 467.41 2  7.19 Papp A-->B: 5.47; Papp B-->A:3.28; Eflux ratio: 0.60

WZ-I- 81  5.36 4.99 51.92 481.44 1  7.53 ++  1

WZ-I- 89  5.36 4.99 51.92 481.44 1  7.53 ++  1

WZ-I- 190- 2  6.55 6.55 80.67 501.58 0 +  2

WZ-I- 236  5.07 3.81 59.43 493.45 2  8.66 —  2

WZ-I- 244  5.18 3.91 50.64 519.49 1  8.69 ++ 2, 3

WZ-I- 243  5.7 4.42 50.64 533.51 1  8.69 ++  2

WZ-I- 249  7.08 4.6 50.64 547.54 1  8.66 ++  2

WZ-I- 283  4.94 3.85 76.94 577.52 1  8.47 +  4

WZ-I- 298  5.14 3.96 59.87 549.51 1  8.58 +  4

WZ-I- 300  5.66 3.93 70.87 597.98 2  8.39 ++++ 4, 9

WZ-I- 310  8.63 4.85 86.17 649.63 1  9.23 +  7

WZ-II- 2  6.86 1.88 73.24 469.61 2  8.81 —  7

WZ-II- 39-1  6.49 4.59 50.56 506.49 2  9.04 +++  5 diastereo- mer 1

WZ-II- 39-2  6.49 4.59 50.56 506.49 2  9.04 ++  5 diastereo- mer 2

WZ-II- 70  6.7 3.81 76.86 564.52 2  9.59 +++  6 mixture of diastereo-mers

WZ-II- 92  5.97 4.29 50.64 533.51 1  8.72 ++  8 mixture of diastereo-mers

WZ-II- 93  5.97 4.32 70.87 612.01 2  8.43 ++++ 8, 9 mixture ofdiastereo- mers

WZ-II- 98  6.65 4.79 70.87 638.05 2  8.44 +++  9

WZ-II- 104  7.25 4.82 50.64 559.55 1  8.87 +  9

WZ-II- 124  6.29 4.23 59.87 563.54 1  8.68 ++ 10

WZ-II- 129  5.28 3.69 70.87 563.54 2  8.62 +++ 10

WZ-II- 149  5.31 5.38 51.92 495.46 1  7.56 ++++ 11 Plasma PK (5mpk IV)HL_ Lambda_z 41.667647 min, Tmax 10 min, Cmax 1046.6667 ng/mL, AUClast67665.865 min*ng/ml, Vz_F_obs 101565.51 mL, Cl_F_obs 1689.5566 mL/min;Plasma PK (10 mpk IP) HL_ Lambda_z 38.91983 min, Tmax 10 min, Cmax638.0333 ng/mL, AUClast 60049.5 min*ng/ml, Vz_F_obs 208114 mL, Cl_F_obs3706.43 mL/min; Brain PK (5mpk IV), HL_ Lambda_z 133.1075 min, Tmax 10min, Cmax 1297.933 ng/mL, AUClast 76594.69 min*ng/ml, Vz_F_obs 286490.1mL, Cl_F_obs 1491.875 mL/min; Brain PK (10 mpk IP), HL_ Lambda_z64.37396 min, Tmax 10 min, Cmax 77.79233 ng/mL, AUClast 8061.515min*ng/ml, Vz_F_obs 2306714 mL, Cl_F_obs 24837.56 mL/min; 1.13;diastereo- mer 1; diastereo- mer of WZ-II-231

WZ-II- 150  5.87 3.59 59.87 561.52 1  8.57 +++ 11

WZ-II- 151  6.18 3.97 59.87 575.55 1  8.6 +++ 11 Plasma PK (5 mg/ Kg IV)T1/2 131 min, Tmax 10 min, Cmax 869 ng/mL, AUClast 54500 min*ng/ml,Vz_F_obs 453 mL, Cl_F_obs 2.39 mL/min; Brain PK (5 mg/ Kg IV), T1/2 269min, Tmax 10 min, Cmax 22.7 ng/mL, AUClast 5585 min*ng/ml, Vz_F_obs 8876mL, Cl_F_obs 22.9 mL/min; mixture of diastereo- mers

WZ-II- 174  5 3.8 70.87 577.57 2  8.63 ++ 12 mixture of diastereo- mers

WZ-II- 184- 1  6.19 2.55 76.66 655.48 2  8.25 + 12 mixture of diastereo-mers

WZ-II- 184- 2  6.17 1.18 62.67 574.57 2  8.6 + 12 mixture of diastereo-mers

WZ-II- 186  4.32 3.75 92.02 538.49 3  7.34 + 12 diastereo- mer 1

WZ-II- 187  4.32 3.75 92.02 538.49 3  7.34 ++++ 12 diastereo- mer 2

WZ-II- 205  4.91 3.96 83.23 552.52 2  7.38 ++ 13 diastereo- mer 1

WZ-II- 206  4.91 3.96 83.23 552.52 2  7.38 +++ 13 diastereo- mer 2

WZ-II- 207  5.21 4.38 59.87 577.57 1  8.56 +++ 13 mixture of diastereo-mers

WZ-II- 208- 1  4.43 4.68 72.23 576.54 1  6.9 + 13 diastereo- mer 1

WZ-II- 209- 1  4.43 4.68 72.23 576.54 1  6.9 +++ 13 diastereo- mer 2

WZ-II- 208- 2  4.61 4.87 83.23 657.45 2  6.59 + 13 diastereo- mer 1

WZ-II- 209- 2  4.61 4.87 83.23 657.45 2  6.59 +++ 13 diastereo- mer 2

WZ-II- 229  6.29 3.65 70.87 549.51 2  8.67 +++ 14 mixture of diastereo-mers

WZ-II- 230  6.52 4.06 74.43 FALSE 1  8.61 ++++ 14 mixture of diastereo-mers

WZ-II- 231  5.31 5.38 51.92 495.46 1  7.56 +++ 14 diastereo- mer 2;diastereo- mer of WZ-II-149;

WZ-II- 252  5.02 4.52 86.79 559.51 1  6.9 +++ 15 diastereo- mer 1

WZ-II- 253  5.02 4.52 86.79 559.51 1  6.9 ++++ 15 Plasma PK (5 mg/ KgIV) T1/2: 40 min, Tmax 10 min, Cmax 651 ng/mL, AUClast 31089 min*ng/ml,Vz_F_obs 221 mL, Cl_F_obs 3.86 mL/min; Brain PK (5 mg/ Kg IV), T1/2: 47min, Tmax 10 min, Cmax 218 ng/mL, AUClast 12554 min*ng/ml, Vz_F_obs 642mL, Cl_F_obs 9.5 mL/min; diastereo- mer 2

WZ-II- 264  5.55 5.81 45.14 496.45 0 N/A — 16 single diastereo- mer

WZ-II- 269  4.55 4.9 62.92 481.44 2  7.23 + 17 diastereo- mer 1

WZ-II- 270  4.55 4.9 62.92 481.44 2  7.23 + 17 diastereo- mer 2

WZ-III- 10  4.92 5.22 75.71 534.5 1  7.45 + 18 diastereo- mer 1

WZ-III- 11  4.92 5.22 75.71 534.5 1  7.45 ++++ 18 diastereo- mer 2

ARN- 1-17  4.56221 2.46 72.15 402.49 2  9.04 —  1

ARN- 1-19  2.52521 0.69 79.66 388.46 3  9.2 —  1

ARN- 1-28  4.56221 2.51 72.15 402.49 2  8.98 +  1

ARN- 1-29  2.52521 0.9 79.66 388.46 3  9.17 —  1

ARN- 1-37  4.28221 2.7 72.15 412. 4837 2  8.93 —

ARN- 1-85  4.73942 2.08 70.79 387.47 3  8.96 + Same as ARN-110

ARN- 1-99  4.28942 2.73 92.38 448.1 3  7.99 —

ARN- 1-110  4.73942 2.08 70.79 387.47 3  8.96 + Same as ARN-85

ARN- 1-163  5.99661 3.67 39.56 385.5 1  9.31 +

ARN- 1-174  4.99861 2.7 51.92 400.51 1  9.11 — named as ARN-173 inactive assignment summary;

ARN- 1-199  4.90082 3.01 59.79 401.5 2  8.99 —  4

ARN- 1-212  4.90082 3.01 59.79 401.5 2  8.99 +  4

ARN- 1-223  4.99861 2.98 51.92 400.51 1  8.92 +  4

ARN- 1-229  4.99861 2.75 51.92 400.51 1  9.09 —  4

ARN- 1-237  5.93461 4.4 51.92 442.57 1  8.69 ++

ARN- 1-238  6.94461 4.74 39.56 413.57 1  9.25 +

ARN- 1-243  4.04161 3 64.28 401.5 1  8.96 +

ARN- 1-255  5.64261 3.6 39.56 391.53 1  9.12 +  6

ARN- 1-256 (568, 574)  6.49561 4.23 39.56 399.53 1  9.25 ++  6 PappA-->B: 7.37; Papp B-->A: 4.91; Eflux ratio: 0.67; aka ARN-1- 568 andARN-1- 574

ARN- 1-260  5.88361 3.87 51.92 436.55 1  9.25 —  6

ARN- 1-265  5.29661 3.64 51.92 420.93 1  8.87 ++

ARN- 1-267  6.36161 3.96 51.59 438.56 1  9.44 + <90% pure, broad peak innmr

ARN-1- 269  6.67492 5.19 51.92 477.02 1  8.48 +

ARN-1- 279  6.82492 5.49 51.92 521.47 1  8.32 —

ARN-1- 284  6.10492 4.67 51.92 460.56 1  8.55 +

ARN-1- 288  6.56755 5.39 61.15 486.99 1  8.37 —

ARN-1- 303  6.70961 4.51 39.56 419.94 1  9.01 ++

ARN-1- 306  6.28561 4.83 39.56 439.47 1  8.72 —

ARN-1- 307  6.21261 4.29 39.56 421.48 1  8.89 +

ARN-1- 311  6.87961 4.9 39.56 453.5 1  8.87 ++  8 data only

ARN-1- 312  6.85261 4.81 39.56 437.67 1  8.83 ++  8 data only

ARN-1- 313  7.30261 5.31 39.56 454.39 1  8.79 ++  8 data only

ARN-1- 316  5.42961 3.71 63.35 410.51 1  9.07 +  8 data only

ARN-1- 317  7.00261 5.11 39.56 482.38 1  8.68 ++  8 data only

ARN-1- 320  6.29261 4.79 63.35 489.41 1  8.72 —  9

ARN-1- 321  7.00261 5.07 39.56 482.38 1  8.72 +  9

ARN-1- 328  6.55561 4.51 39.56 431.59 1  9.05 ++ 10

ARN-1- 333  7.82261 5.4 39.56 441.61 1  9.07 ++ 10

ARN-1- 337  7.02461 5.53 48.79 469.5 1  8.78 + 10

ARN-1- 338  5.42961 3.7 63.35 410.51 1  9.09 ++ 10

ARN-1- 344  6.87961 4.87 39.56 453.5 1  8.91 +

ARN-1- 350  2.52521 3.05 79.66 371.47 2  9.28 +

ARN-1- 353  6.30561 4.08 39.56 399.2 1  9.32 ++ 12

ARN-1- 362  6.85261 4.8 39.56 437.2 1  8.84 + 12

ARN-1- 366  8.74601 6.64 39.56 489.3 1  9.03 + 13

ARN-1- 374  5.73821 3.61 50.56 385.2 2  9.22 + 14

ARN-1- 375  8.80601 6.86 39.56 521.3 1  8.91 + 14

ARN-1- 376  8.74601 6.64 39.56 489.3 1  9.03 + 14

ARN-1- 387  6.454 5.37 18.84 367.2 0 + 15

ARN-1- 388 (525, 557)  5.738 3.61 50.56 385.5 2  9.22 ++ 15 aka ARN-1-525 and ARN-1- 557

ARN-1- 392  9.10301 7.11 39.56 527.2 1  8.76 + 15

ARN-1- 409  6.88461 4.59 39.56 413.5 1  9.24 +++ 16

ARN-1- 414  7.41361 5.14 39.56 427.3 1  9.21 ++ 16

ARN-1- 422  6.36001 4.28 48.79 443.3 1  9.13 +++ 16

ARN-1- 424  9.67401 7.37 39.56 517.3 1  9.03 +

ARN-1- 441  4.71706 2.8 28.07 307.2 0 —

ARN-1- 452  6.76901 2.95 42.8 456.6 1  9.3 + 18

ARN-1- 460  6.69381 4.27 65.86 471.6 1  9.02 ++ 18

ARN-1- 485 10.013 8.37 39.56 611.6 1  8.47

ARN-1- 496  6.87061 4.38 48.79 457.6 1  9.07 ++ 19

ARN-1- 524  6.23721 4.07 50.56 399.5 2  9.29 + 20

ARN-1- 525 (388, 557)  5.738 3.61 50.56 385.5 2  9.22 ++ 20 AKA ARN-1-388 and ARN-1- 557

ARN-1- 527  6.99461 4.69 39.56 413.5 1  9.32 +

ARN-1- 528  6.62121 4.91 50.56 453.5 2  8.72 + 20

ARN-1- 531  7.37861 4.8 39.56 467.5 1  8.76 + 20

ARN-1- 535  5.88121 4.84 50.56 403.5 2  7.93 ++ 20

ARN-1- 541  6.63861 5.46 39.56 417.5 1  7.97 ++ 21

ARN-1- 545  6.23721 4.1 50.56 399.5 2  9.25 + 21

ARN-1- 547  8.25461 5.97 28.07 481.5 0 + 21 named as ARN-546 in graphic

ARN-1- 557 (388, 525)  5.738 3.61 50.56 385.5 2  9.22 ++ 22 AKA ARN-1-388 and ARN-1- 525

ARN-1- 567  7.37161 4.65 28.07 413.5 0 ++ 22

ARN-1- 568 (574, 256)  6.49561 4.23 39.56 399.53 1  9.25 +++ 22 AKAARN-1- 256 and ARN-1- 574

ARN-1- 572  6.62121 4.91 50.56 453.5 2  8.72 + 23

ARN-1- 574 (568, 256)  6.49561 4.23 39.56 399.53 1  9.25 +++ 23 akaARN-1- 256 and ARN-1- 568

ARN-1- 575  7.37861 5.51 39.56 467.5 1  8.76 + 23

ARN-1- 583  6.23721 4.1 50.56 399.5 2  9.25 ++ 24

ARN-1- 586  6.99461 4.72 39.56 413.5 1  9.28 ++ 24

ARN-1- 589  6.62121 4.91 50.56 453.5 2  8.72 — 25

ARN-1- 592  7.37861 5.51 39.56 467.5 1  8.76 — 25

ARN-1- 603  6.23721 4.07 50.56 399.5 2  9.29 ++ 25

ARN-1- 608  6.99461 4.69 39.56 413.6 1  9.32 ++ 25

ARN-1- 611  6.71161 5.45 39.56 435.5 1  8.15

ARN-1- 626  6.45121 4.74 50.56 419.9 2  8.6 ++ 26

ARN-1- 629  7.20861 5.35 39.56 434 1  8.64 + 26

ARN-1- 632  7.35861 5.42 39.56 478.4 1  8.74 ++ 26

ARN-1- 642  7.80161 6.39 39.56 468.4 1  8.13 + 27

ARN-1- 643  7.35861 5.42 39.56 478.4 1  8.74 +++ 27

ARN-1- 757  7.18221 5.16 39.56 459.6 1  9.07 + 28

ARN-1- 761  7.93521 5.9 39.56 499.27 1  9.2 + 28 Purity <80% Mixture DM

ARN-1- 770  3.9066 1.48 87.74 403.6 2 +++ 29

ARN-1- 771  3.9066 1.48 87.74 403.6 2

ARN-1- 776  3.9066 1.48 87.74 403.6 2 ++++ + 31

ARN-1- 795  6.62545 5.39 48.3 429.55 1 + 29

ARN-1- 805  7.11301 5.02 48.79 483.6 1  9.25 ++++ 29 Mixture of DM

ARN-1- 826  7.00241 5.1 48.79 469.6 1  9.3 +++ 30 Purity <80% Mixture ofDM

ARN-1- 846  6.55 4.33 59.71 469.63 2  9.31 +++ 31 named as ARN in graph

ARN-1- 851  7.39351 4.59 56.63 467.6 1  9.64 +++ 33 Mixture of DM

ARN-1- 855  7.97751 5.41 56.63 574.56 1  9.59 ++ 34 Mixture of DM

ARN-1- 857  8.01251 4.36 59.87 522.29 1  9.49 ++ 34 Mixture of DM

ARN-1- 861  7.25651 3.15 76.94 550.69 1  9.26 ++++ 34 Mixture of DM

ARN-1- 909  6.22204 3.46 72.15 454.56 2  9.24 ++ 35 Mixture of DM

ARN-1- 931  5.06141 5.49 61.15 535.49 1  7.5 + 36 Diastereo- mers-1

ARN-1- 932  5.06141 5.49 61.15 535.49 1  7.5 +++ 36 Diastereo- mers-2

ARN-1- 946  5.17201 5.4 61.15 539.52 1  7.46 ++ 37 Diastereo- mers-1

ARN-1- 947  5.17201 5.4 61.15 539.52 1  7.46 ++++ 37 Diastereo- mers-2

ARN-1- 956  4.10861 4.66 64.28 516.87 1  7.2 + 37 Diastereo- mers-1

JECO- 023  7.14871 4.93 30.33 415.6 1  9.44 ++ 1, 2

JECO- 036  7.67771 5.18 30.33 429.6 1  9.43 ++  2

JECO- 037  7.98671 5.5 30.33 443.7 1  9.43 ++  2

JECO- 038  5.34691 2.74 64.47 447.6 1  9.56 ++ 2, 3 sulfone

JECO- 044  5.43931 2.56 47.4 431.6 1  9.67 ++  3 sulfoxide

MKG- 25  5.31 5.38 51.92 414.55 1  7.56 ++++  4 diastereo- mer 2; thefree base of WZ-II-149

MKG- 26  5.31 5.38 51.92 414.55 1  7.56 ′+++  4 diastereo- mer 1; thefree base of WZ-II-231 + Increases beyond 1 μM; does not saturate; ++EC50 2 μM to 8 μM, saturation but Emax <OXB; +++ EC50 1-2 μM, Emax nearOXB; ++++ EC50 less than 1 μM, Emax near OXB; In the test resultgraphics, ww4-126 is the compound 26 in J. Med. Chem. 2015, 58,7931-7937.

TABLE 2 New Analogs

TABLE 3

TABLE 4 Series 3

Ar =

  R_(x) = F, tBu, CN, Br, CF₃, SMe, Cl, Me R_(xi) = CN, CF₃, Cl, F, Me,H

R_(i) = H, Me, CF3, Et, iPr, cPr, cBu, CH2F R_(ii) = H, Me R_(iii) = H,Me, Et, Pr, —CH₂OMe, —CH₂CH₂OMe, —CH₂CH₂OH, —(CH₂)₃OMe, —CO₂Me,—C(O)CH₂OH, Ac, —CH₂C(O)Me, —CH₂(4-MePh), —CH₂(4-MeSPh), —CH₂(3-Cl,4-FPh), —CH₂(4-iPrPh) R_(iv) = H, Me R_(xi) = H, Me Y CH, N, CMe, CF XCH, N, CMe, CF

TABLE 5 Series 3A

Ar =

R_(i) = Me, Et, cPr R_(ii) = H, Me R_(iii) = H, Me, Et, Pr, —CH₂OMe,—CH₂CH₂OMe, —CH₂CH₂OH, R_(iv) = Me R_(xi) = H Y CH, N, X CH, N,

TABLE 6 Ether Series

Ar =

  R_(x) = Cl, Me R_(xi) = Cl, F, Me, H  

R_(i) = Me, Et, cPr, R_(ii) = H, Me R_(iii) = H, Me, Et, Pr, —CH₂OMe,—CH₂CH₂OMe, —CH₂CH₂OH, R_(iv) = Me R_(xi) = H Y CH, N, CF X CH, N, CFEther Series B

Ar =

 

R_(i) = Me, Et, cPr, R_(ii) = H, Me R_(iii) = Me, Et, —CH₂CH₂OMe, R_(iv)= Me R_(xi) = H Y CH, N X CH, N

TABLE 7 Series 2

R_(i) = H, Me, CF₃, Et, iPr, cPr, cBu, CH₂F R_(ii) = H, Me R_(vi) =—CH₂OH, aziridin-2-yl, NH₂, —CHMeOH (S), —CMeOH (R), NHMe, —CH₂NH₂,—CH₂NHMe, —CH₂NMe₂, —CH₂OMe, —(CH2)₃OH, H, Me, CF₃, Et, —CH₂F, cPt, OEt,NMe₂, OH, Ph, Bn, 4-MeBn, 4- MeOBn, 4-NH₂Bn, 3-NH₂Bn, 2-NH₂Bn, —CH═CHMe,—CH₂(pyridine-2-yl), —CH₂(pyridin-4yl), —CH₂(3-pyridinyl),—CH₂(pyrimidin-2-yl), oxazol-2-yl, furan-2-yl, oxetan-3-yl,pyrdiine-3-yl, 6-Me-pyridin-2-yl, 3-Me-pyridin-2-yl, pyridazin-3-yl,isoxazol-5-yl, 5-Me-isoxazol-4-yl, 1,4-Me₂-imidazol-5-yl,—CH₂(pyrrol-1-yl), 3,4-Cl₂Bn R_(v) H, Me

TABLE 8 Series 2B

R_(i) = H, Me, CF₃, Et, iPr, cPr, cBu, CHF R_(ii) = H, Me R_(vi) =—CH₂OH, aziridin-2-yl, NH₂, —CHMeOH (S), R_(v) H, Me

TABLE 9 Amide (glycoamide) series

R_(i) = Me, cPr, R_(ii) = H, Me R_(vi) = —CH₂OH, aziridin-2-yl, CHMeOH(S), CHMeOH (R), R_(v) H, Me

TABLE 10 Amide (glycoamide) series B

R_(i) = Me, cPr, R_(ii) = H, Me R_(vi) = —CH₂OH, aziridin-2-yl, R_(v) H,Me

TABLE 11 Series 1

R_(i) = H, Me, CF3, Et, iPr, cPr, cBu, CH2F R_(ii) = H, Me R_(ix) =

 

 

TABLE 12 Series 1B

R_(i) = H, Me, CF3, Et, iPr, cPr, cBu, CH2F R_(ii) = H, Me R_(ix) =

 

 

 

TABLE 13 Reverse Amide Series

R_(i) = Me, cPr, c R_(ii) = H, Me R_(ix) =

 

TABLE 14 Series S

R_(i) = H, Me, CF₃, Et, iPr, cPr, cBu, CH₂F R_(ii) = H, Me R_(vii) H, MeR_(vii) = Me, CF₃, CHF₂, Et, cPr, iPr, Bn, Ph

Chemotype 3

SAR on top and bottom aromatic rings exensively explored:

p-Me on both rings highest activity other substituents and variousdi-substituted aryl rings as well as various mono- and bicyclic fused Rheterocycles

SAR results for Chemotype 3

We have identified a hotspot for modifications (R) Large amount ofvariations in R possible (sterics, electronics, amides, reverse amides,ethers . . . ) Potency can be gained here (R) Physiochemical propertiescan be adjusted here (R) Primary amides are not BBB penetrable R EthersBBB penetrable

R═OH BBB penetrable

Inverse secondary amides promising, BBB expected to improve because ofremoval of one H-bond donor NH Introduction of stereogenic R′ improvespotency

Screen for New OXR Agonists

220,000-compound library screened for OX2R activation at 5 uM in a CHONFAT luciferase reporter assay. This assay uses a cell-basedtranscriptional reporter dependent on Gq stimulated Ca²⁺ release due toactivation of a stably transfected Gq-coupled GPCR.

#384-well plates screened: 678

Average Z′ across all plates: 0.758

960 compounds cherry-picked (CPHits) with z-score >2.3

Average z-score of all CPHits in primary screen: 8.119

CPHits were re-screened in duplicate for activation of the NFATluciferase reporter: 72 compounds have z-score >2 (average ofduplicates). 126 compounds have zscore >1 (average of duplicates).

CPHits were counter-screened in duplicate for activation of‘receptor-less’CHO reporter cell line: z-score=−0.291 (average ofduplicates).

CPHits were counter-screened in duplicate for activation of a CRE(Gs/cAMP-dependent) luciferase reporter cell line: z-score=−0.152(average of duplicates).

Compounds remaining after counter-screens were tested in aGRPR-transfected cell line (different neuropeptide-activated Gq-coupledGPCR).

OXR specific agonists curated: rank order in re-screening, drug-likephysical

properties, stability/reactivity, synthetic accessibility.

The examples herein are provided by way of illustration only and not byway of limitation. Those skilled in the art will readily recognize avariety of noncritical parameters that could be changed or modified toyield essentially similar results.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, wherein the disease, disorder, or medical condition is a disorder of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity or a condition related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse, comprising administering to the subject in need thereof an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Y¹ and Y² are each independently N, CH or CR⁶; Ar¹ and Ar² are each independently C5-C10 aryl or 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S, and optionally substituted with one or more R¹⁰; R¹ is —OH, halogen, CN, CH₂CN, —C₁-C₄ alkoxy, —C₁-C₄ haloalkoxy, —NR^(a)R^(b), —NR^(a)COR⁹, —NR^(a)CO(optionally substituted heterocyclyl), SO₂R¹², —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl) or —O—(C₁-C₃ alkylene)-O—(C₁-C₄ haloalkyl); R² is NH or NR¹¹, R³ is H, —OH or methyl; R⁴ is H —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, or —C₃-C₄ cycloalkyl; R⁵ is H, OH, or F; R⁶ is halogen, —CN, —NO₂, —SCH₃, —COR^(g), —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, —C₃-C₄ cycloalkyl, —C₁-C₄ alkoxy, or —C₁-C₄ haloalkoxy; R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆ alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃ alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f), —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)_(n)(cycloalkyl), —CO(CH₂)_(n)(optionally substituted aryl), —CO(CH₂)_(n)(optionally substituted heterocyclyl), —CO(CH₂)_(n)(optionally substituted heteroaryl), or SO₂R¹²; R^(e) and R^(f) are each independently H, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, or —C₁-C₆ alkylene-OH; R^(g) is H, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl, phenyl, or benzyl, R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, —C₁-C₃ alkylene-(C₁-C₃ alkoxy), or —C₁-C₃ alkylene-NR^(a)R^(b), —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, or 2-aziridinyl; R¹⁰ is halogen, —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, —C₁-C₆ haloalkoxy, —S—S—(C₁-C₆ alkyl), or optionally substituted phenyl; R¹¹ is —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, —C₁-C₄ alkoxy, or COO(C₁-C₄ alkyl); R¹² is —OH, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, phenyl, benzyl, —NR^(a)R^(b), —CONR^(a)R^(b), or —NR^(a)COR^(g); n is 0, 1, or
 2. 2. The method of claim 1, wherein each of Ar¹ and Ar² is phenyl optionally substituted with one or more R¹⁰.
 3. The method of claim 1, wherein R¹⁰ is halogen, —CN, —C₁-C₄ alkyl, or —C₁-C₄ fluoroalkyl.
 4. The method of claim 1, wherein each of Ar¹ and Ar² is 4-methylphenyl.
 5. The method of claim 4, wherein: R¹ is —OH, —F, C₁-C₄ alkoxy, —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl) or —O—(C₁-C₃ alkylene)-O—(C₁-C₄ haloalkyl), C₁-C₄ haloalkoxy, —NR^(a)R^(b), —NHCOR⁹, or —NR^(a)CO(optionally substituted heterocyclyl); R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl or —C₁-C₄ fluoroalkyl; and R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-CN, or —C₁-C₃ alkylene-NR^(a)R^(b).
 6. The method of claim 1, wherein: R¹ is —OH, —OCH₃, —F, C₁-C₄ haloalkoxy, —NR^(a)R^(b), —NHCOR⁹, or —OCH₂O—(C₁-C₄ alkyl), —OCH₂O—(C₁-C₄ haloalkyl), or —NR^(a)CO(optionally substituted heterocyclyl); R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl or —C₁-C₄ fluoroalkyl; and R⁹ is —C₁-C₃ alkylene-OH, —C₁-C₃ alkylene-NR^(a)R^(b), —C₁-C₄ alkyl or —C₁-C₄ fluoroalkyl.
 7. The method of claim 1, wherein: R¹ is —OH, —OCH₃, —F, —NHCH₃, —N(CH₃)₂, —NHSO₂R¹², or —NHCOR⁹; and R¹² is —CH₃, —CH₂CH₃, isopropyl, —CF₃, cyclopropyl, phenyl or benzyl; and R⁹ is —CH₂OH, —CH₂NH₂, —CH₂NHMe, —CH₂NMe₂ or 2-aziridinyl.
 8. The method of claim 1, wherein R² is NH.
 9. The method of claim 1, wherein R³ is H.
 10. The method of claim 1, wherein R⁴ is H or methyl.
 11. The method of claim 1, wherein R⁶ is halogen, —CH₃, —CF₃, —CN, —SCH₃, t-butyl, —OCH₃, or —OCF₃, and n is 1 or
 2. 12. The method of claim 1, wherein: Y¹ is CH and Y² is N, CH or CR⁶, wherein R⁶ is halogen; Ar¹ and Ar² are independently 4-MePh, 4-CF₃Ph, 4-Me-2,5-pyrazin-1-yl, 4-Cl-3-pyridin-1-yl, 4-ClPh, 3-F-4MePh, 3-F-4ClPh, 3-F-4BrPh, 3,4-Cl₂Ph, or 3,4-Me₂Ph; R¹ is —OH, —C₁-C₄ alkoxy, —C₁-C₄ haloalkoxy, —NR^(a)COR⁹, or —NR^(a)CO(aziridin-2-yl); R³ is H; R⁴ is H, —C₁-C₄ alkyl, —C₁ haloalkyl, or —C₃ cycloalkyl; R⁵ is H; R⁶ is halogen; R^(a) and R^(b) are each independently H or Me; R⁹ is CH₂OH, CH₂NH₂, CH₂NHMe, CH₂NMe₂, or 2-aziridinyl; and R¹¹ is —C₁-C₄ alkyl, —C₁-C₄ fluoroalkyl, or —C₁-C₄ alkoxy.
 13. The method of claim 1, wherein: R¹ is —OH, —C₁-C₄ alkoxy, —C₁-C₄ haloalkoxy, —NR^(a)R^(b), —NR^(a)COR⁹, —NR^(a)CO(optionally substituted heterocyclyl), SO₂R¹², —O—(C₁-C₃ alkylene)-O—(C₁-C₄ alkyl) or —O—(C₁-C₃ alkylene)-O—(C₁-C₄ haloalkyl); R⁵ is H, and R^(a) and R^(b) are each independently H, —C₁-C₄ alkyl, —C₁-C₄ haloalkyl, —CHO, —CO(C₁-C₃ alkyl), —CO(C₁-C₆ alkylene)-OH, —CONR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)R^(f), —CO(C₁-C₃ alkylene)-NR^(e)SR^(f), —CO(C₁-C₃ alkylene)-NR^(e)SOR^(g), —CO(C₁-C₃ alkylene)-NR^(e)SO₂R^(f), —CO(C₂-C₃ alkenyl), —CO(C₁-C₃ haloalkyl), —CO(CH₂)_(n)(cycloalkyl), —CO(CH₂)_(n)(optionally substituted aryl), —CO(CH₂)_(n)(optionally substituted heterocyclyl), or —CO(CH₂)_(n)(optionally substituted heteroaryl).
 14. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, wherein the disease, disorder, or medical condition is a disorder of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity or a condition related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse, comprising administering to the subject in need thereof an effective amount of a compound of formula I:

or a pharmaceutically acceptable salts thereof, wherein: Y1 and Y2 are independently N, CH or CR6; Ar1 and Ar2 are independently optionally substituted C5-C10 aryl or heteroaryl having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; R1 is optionally substituted, optionally cyclic C1-C10 hydrocarbyl or heterohydrocarbyl, or optionally substituted heteroatom; R2 is NR, wherein R is H, Me, tert-butyloxycarbonyl (Boc), optionally fluorinated C1-C4 alkyl, C1-C4 alkyloxy, or C1-C4 alkyloxycarbonyl; R3 is H or Me; R4 is H or optionally fluorinated C1-C4 alkyl or —C₃-C₄ cycloalkyl, or cyano, nitro, carboxyl or acetyl; R5 is H or Me; each R6 is independently halide, optionally fluorinated C1-C4 alkyl or —C₃-C₄ cycloalkyl or cyano, nitro, carboxyl acetyl, SMe, OCF₃ or OMe; n is an integer 0-2.
 15. The method of claim 14, wherein each of Ar1 and Ar2 is optionally substituted phenyl.
 16. The method of claim 14, wherein each of Ar1 and Ar2 is phenyl, optionally substituted with halo, cyano, or optionally fluorinated C1-C4 alkyl.
 17. The method of claim 14, wherein each of Ar1 and Ar2 is 4-methyl phenyl.
 18. The method of claim 14, wherein R1 is amide, amine, hydroxyl or hydrocarbyloxy.
 19. The method of claim 14, wherein R1 is OR, NRR, NHCOR, or CONRR, wherein each R is independently H or optionally fluorinated C1-C4 alkyl.
 20. The method of claim 14, wherein R1 is OH, OMe, OR, NRR, CONRR, NHC(O)R, wherein each R is independently H or optionally fluorinated C1-C4 alkyl.
 21. The method of claim 14, wherein R1 is OH, OMe, NHMe, NMe₂, NHSO₂R16 or NHCOR16, where R16 is Me, CF₃, OH, OMe, OEt, ethyl, phenyl, cyclo propyl, isopropyl, benzyl, NH₂, NRR, CONR2 or NHC(O)R, wherein each R is independently H or optionally fluorinated C1-C4 alkyl.
 22. The method of claim 14, wherein R2 is NH or NMe.
 23. The method of claim 14, wherein R2 is NH.
 24. The method of claim 14, wherein R3 is H.
 25. The method of claim 14, wherein R4 is H, Me, Et, CF₃, isopropyl, cyclopropyl or cyclobutyl.
 26. The method of claim 14, wherein R4 is H or Me.
 27. The method of claim 14, wherein R5 is H.
 28. The method of claim 14, wherein each R6 is independently Me, Et, CF₃, isopropyl, cyclopropyl, cyclobutyl, cyano, nitro, carboxyl, acetyl, halide, SMe, t-butyl, OCF₃ or OMe.
 29. The method of claim 14, wherein the compound is of the structure:

wherein, Ar is selected from: 4-MePh, 4-CF₃Ph, 4-Me-2,5-pyrazin-1-yl, 4-Cl-3-pyridin-1-yl, 4-ClPh, 3-F-4MePh, 3-F-4ClPh, 3-F-4BrPh, 3,4-Cl₂Ph, or 3,4-Me₂Ph; Rxi is Br, Cl, CF₃, F, Me or H; R_(i) is H, Me, CF₃, Et, iPr, cPr, cBu or CH₂F; R_(ii) is H or Me; R_(iii) is H, Me, Et, Pr, —CH₂OMe, —CH₂CH₂OMe, —CH₂CH₂OH, —(CH₂)₃OMe, —CO₂Me, —C(O)CH₂OH, Ac, —CH₂C(O)Me, —CH₂(4-MePh), —CH2(4-MeSPh), —CH₂(3-Cl, 4-FPh), or —CH₂(4-iPrPh); R_(iv) is Cl or Me; Y is CH, N, CMe or CF; and Z=CH, N, CMe or CF.
 30. The method of claim 14, wherein the compound is of the structure:

wherein, Ar is

Ri is Me, Et or cPr; Rii is H or Me; Riii is H, Me, Et, Pr, —CH2OMe, —CH₂CH₂OMe, or —CH₂CH₂OH; Riv is Me; Rxi is H; Y is CH, or N; and Z is CH or N.
 31. The method of claim 14, wherein the compound is of the structure:

wherein, Ar is

Rx is Cl or Me; Rxi is Cl, F, Me or H; Ri is Me, Et or cPr; Rii is H or Me; Riii is H, Me, Et, Pr, —CH2OMe, —CH2CH2OMe, or —CH2CH2OH; Riv is Me; Rxi is H; Y is CH, N or CF; and Z is CH, N or CF.
 32. The method of claim 14, wherein the compound is of the structure:

wherein, Ar is

Ri is Me, Et or cPr; Rii is H or Me; Riii is Me, Et, or —CH₂CH₂OMe; Riv is Me; Rxi is H; Y is CH or N; and Z is CH or N.
 33. The method of claim 14, wherein the compound is of the structure:

wherein, Y=N, CH, or CF; Ri is H, Me, CF₃, Et, iPr, cPr, cBu, or CH₂F; Rii is H or Me; Rv is H or Me; R_(vi) is —CH₂OH, aziridin-2-yl, NH₂, —CHMeOH (S), —CHMeOH (R), NHMe, —CH₂NH₂, —CH₂NHMe, —CH₂NMe₂, —CH₂OMe, —(CH₂)₂OH, —(CH₂)₃OH, H, Me, CF₃, Et, CHF₂, CH₂F, cPr, OEt, NMe₂, OH, Ph, Bn, 4-MeBn, 4-MeOBn, 4-NH2Bn, 3-NH₂Bn, 2-NH₂Bn, —CH═CHMe, —CH₂(pyridine-2-yl), CH₂(pyridin-4-yl), CH₂(3-pyridinyl), CH₂(pyrimidin-2-yl), oxazol-2-yl, furan-2-yl, oxetan-3-yl, pyridine-3-yl, 6-Me-pyridin-2-yl, 3-Me-pyridin-2-yl, pyridazin-3-yl, isoxazol-5-yl, 5-Me-isoxazol-4-yl, 1,4-Me₂-imidazol-5-yl, —CH₂(pyrrol-1-yl) or 3,4-Cl₂Bn.
 34. The method of claim 14, wherein the compound is of the structure:

wherein, Y=N, CH, or CF; R_(i) is H, Me, CF₃, Et, iPr, cPr, cBu or CH₂F; R_(ii) is H or Me; R_(v) is H or Me; and R_(vi) is —CH₂OH, aziridin-2-yl, NH₂, or —CHMeOH (S).
 35. The method of claim 14, wherein the compound is of the structure:

wherein, Y=N, CH, or CF; R_(i) is Me or cPr; R_(ii) is H or Me; R_(v) is H or Me, and R_(vi) is —CH₂OH, aziridin-2-yl, CHMeOH (S) or CHMeOH (R).
 36. The method of claim 14, wherein the compound is of the structure:

wherein, Y=N, CH, or CF; R_(i) is Me or cPr; R_(ii) is H or Me; R_(v) is H or Me; and R_(vi) is —CH₂OH or aziridin-2-yl.
 37. The method of claim 14, wherein the compound is of the structure:

wherein, Y=N, CH, or CF; R_(i) is H, Me, CF₃, Et, iPr, cPr, cBu, or CH₂F; R_(ii) is H or Me; R_(vii) is H or Me; and R_(viii) is Me, CF₃, CHF₂, Et, cPr, iPr, Bn or Ph.
 38. The method of claim 1, for increasing resistance to diet-induced accumulation of body fat, in a subject in need thereof.
 39. The method of claim 1, for shortening recovery period from general anesthesia or jet lag, in a subject in need thereof.
 40. The method of claim 1, for treating narcolepsy, in a subject in need thereof. 